NIAMS Long-Range Plan: Fiscal Years 2010-2014

February 1, 2010

PDF version of this document
Brochure of Long-Range Plan (PDF)
Introduction from the Director, Stephen I. Katz, M.D., Ph.D.

Executive Summary
Cross-cutting Topics
I. Health Disparities
II. Training and Career Development
III. Infrastructure
IV. Information Dissemination

Disease- and Tissue-specific Topics
I. Arthritis and Rheumatic Diseases
Genetics and Genomics
Mechanisms of Disease
Preclinical and Translational Research
Clinical Research
Behavioral and Biopsychosocial Research

II. Skin Biology and Diseases
Biology and Heritable Diseases of Skin
Immunobiology and Immune Mediated Diseases of Skin
Wound Healing and Regenerative Medicine
Model Systems and Therapy Development
Clinical Research
Behavioral and Biopsychosocial Research

III. Bone Biology and Diseases
Biology and Physiology of Bone
Developmental Biology and Stem Cells
Imaging and Biomarkers of Bone Quality and Fracture Risk
Preclinical and Translational Research
Clinical Research

IV. Muscle Biology and Diseases
Biology and Physiology of Muscle
Imaging and Biomarkers
Model Systems and Therapy Development
Clinical Research

V. Musculoskeletal Biology and Diseases
Biology, Structure, and Function
Regenerative Medicine and Orthopaedic Implants
Imaging and Biomarkers
Clinical Research


Executive Summary

This is an extraordinary time for biomedical research and for the National Institutes of Health (NIH). Advances in knowledge and technology have shifted the ground beneath the research enterprise, as new combinations of scientists introduce us to a range of questions once unthinkable. The potential for artificial organs, person-tailored prescriptions, and community-targeted prevention strategies provides hope to those with disabling conditions that affect bones, joints, muscles, and skin. Once futuristic, such goals are now realistic, and each can be achieved by matching creative minds with the resources and intellectual freedom to make progress. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Long-Range Plan for FY 2010-2014 is a tool, not a destination, for individual investigators to use their ingenuity to explore the unknown and confront these pressing problems.

In keeping with the rapid evolution of science, novel assemblies of researchers and disciplines are increasingly important for addressing diseases and co-morbidities relevant to the mission of the NIAMS. Like all NIH components, the NIAMS participates in agency-wide projects and solicitations that address scientific and health issues that go beyond a single Institute's interest. By funding research that is complementary to programs supported by other NIH Institutes and Centers, the NIAMS broadens the impact of scientific advances and continues toward the goal of improving the quality of life of all Americans affected by diseases of the bones, joints, muscles, and skin. As these opportunities have increased in recent years as a result of the NIH Roadmap for Medical Research and other collaborative endeavors, NIAMS grantees have been effective leaders, underscoring the strength of our grantee community.

The five disease- or tissue-specific areas represented in the NIAMS Long-Range Plan for FY 2010-2014 cover the Institute's broad mission. They are: Arthritis and Rheumatic Diseases; Skin Biology and Diseases; Bone Biology and Diseases; Muscle Biology and Diseases; and Musculoskeletal Biology and Diseases. However, shifts in modern science have brought to light the importance of acknowledging trans-disciplinary areas and approaches. Many of the complex diseases and conditions relevant to the NIAMS mission can be seen through a new lens using genome-wide analyses, novel behavioral/biopsychosocial research methods, systems biology approaches, and new imaging modalities. In addition, several recurrent themes thread through NIAMS-supported research indicating areas of particular promise, including pharmacogenomics, immunomodulation, epigenomics, stem cells, and tissue engineering. In addition to these scientific themes, cross-cutting topics are highlighted in the NIAMS Long-Range Plan for FY 2010-2014, highlighting needs and opportunities that are relevant to many NIAMS research communities:

Health Disparities. Several diseases and conditions within the NIAMS mandate affect women and minorities disproportionately, and, in many cases, these individuals also suffer worse outcomes. As noted in this plan, uncovering the roots of gender, racial and ethnic disparities are critical to the ability to devise effective strategies to treat and prevent them.

Training and Careers. The Institute is keenly aware of the importance of nurturing a healthy and diverse pipeline of biomedical and behavioral scientists that mirrors the population distribution of America. Fostering early-stage investigators is a key goal of NIAMS and of the NIH as a whole. The Institute embraces various training and career programs that address the needs of both new scientists as well as those in mid-career that benefit from cross-training in new disciplines.

Infrastructure. Although science is foremost a human pursuit, steady progress requires access to cutting-edge technology and other resources. NIAMS staff members continually seek input from the scientific community and other stakeholders on a wide range of infrastructure needs. In this plan, the Institute acknowledges its role in providing access to shared resources such as state-of-the-art instrumentation, patient registries and databases, as well as in facilitating the development of clinical trial and other consortia.

Information Dissemination and Outreach. A critical part of the research process is getting the word out--communicating research results to people who are affected by bone, muscle, joint, or skin diseases. As detailed in this plan, the NIAMS remains committed to working closely with stakeholders to communicate research findings to varied audiences. These efforts also offer the Institute a vehicle for bidirectional communication to foster dialogue on the future path of NIAMS-funded research.

Importantly, the intensive and thorough effort that went toward developing the NIAMS Long-Range Plan for FY 2010-2014, and plans before it, continues. As with past plans, the Institute's overarching goal remains the same: to continue to work with other NIH components and Federal agencies, voluntary and professional groups, individual scientists, and industry to advance biomedical research toward improving public health.


As the primary Federal agency that supports medical research on diseases of the bones, joints, muscles, and skin, the NIAMS touches the lives of nearly every American. Most of these diseases are chronic and many cause life-long pain, disability, or disfigurement. Some are rare, while others are remarkably common. Combined, they afflict tens of millions of Americans, cause tremendous human suffering, and cost the United States economy billions of dollars in health care and lost productivity. For example, the U.S. Bone and Joint Decade notes that one in two people will experience back pain each year, and one in five will have pain that affects their ability to work1. The National Arthritis Data Working Group estimates that 21 percent of adults have arthritis in at least one joint, a figure that is likely to grow as the population ages2. Likewise, one of every two women and one in four men aged 50 years and older suffer fractures because of osteoporosis; researchers project that the number of osteoporotic fractures in the United States will grow from 2 million to more than 3 million in the next two decades3. Although often thought of as a single rare disease that confines young boys to wheelchairs, more than 30 different muscular dystrophies can occur in members of either sex, appear at various life stages, and affect different muscles. Some are progressively disabling but do not directly shorten a person's lifespan, while others cause children to die in infancy. Atopic dermatitis (eczema) is a very common, inflammatory skin disease that affects up to 20 percent of children worldwide4. It can continue into adulthood, and has an economic impact in the billions of dollars5. Fibromyalgia syndrome affects approximately 2 percent of the U.S. population. It is much more common in women than men and is associated with substantial morbidity and disability.

The mission of the NIAMS is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. It is critical to revisit our program areas periodically because research needs, opportunities, and challenges change. The NIAMS Long-Range Plan for FY 2010-2014 will facilitate communication between the Institute and its constituents—scientific communities, patient advocacy organizations, and the Congress—about needs and opportunities related to the NIAMS mission.

The NIAMS Long-Range Plan for FY 2010-2014 is not meant to replace the previous plan but, instead, to continue to promote exploration of ideas and encourage new research directions as needed. Although the NIAMS will continue to devote the majority of its extramural budget toward funding the best investigator-initiated research ideas, we must also continue to rise to the challenge of serving the scientific community in the best possible way. The plan brings attention to many areas that need to be addressed in the coming years in order to propel research progress related to the understanding, diagnosis, treatment and ultimately, prevention, of diseases within NIAMS mission areas.

The plan is not comprehensive; it does not mention every research area or disease of interest by name. As a broad scientific outline for the NIAMS, however, it informs the Institute's priority setting process while enabling the Institute to adapt to the rapidly changing biomedical and behavioral science landscapes.

Through good stewardship of taxpayer dollars, the NIAMS promotes exploration of a broad spectrum of highly meritorious research. To facilitate this process, the NIAMS will continue to partner with a variety of public and private organizations to advance research within our mission areas. Through these efforts, the NIAMS will be able to leverage existing resources and explore many scientific areas in ways that the Institute would not be able to do alone. By funding research that is complementary to programs supported by other NIH Institutes and Centers, the NIAMS will be able to broaden the impact of scientific advances and continue toward our goal of improving the quality of life of all Americans affected by diseases of the bones, joints, muscles, and skin.

1 The Burden of Musculoskeletal Diseases in the United States. The U.S. Bone and Joint Decade. 2008.
2 Helmick CG, et al.; National Arthritis Data Workgroup. Arthritis Rheum. 2008. PMID: 18163481
3 Burge R, et al. J Bone Miner Res. 2007. PMID: 17144789
4 DeBenedetto A, et al. J. Invest. Dermatol. 2009. PMID: 19078985
5 Bickers DR, et al. J. Am. Acad. Dermatol. 2006. PMID: 16908356

Cross-cutting Topics

The NIAMS Long-Range Plan for FY 2010-2014 is organized into five disease- and tissue-specific topics—Arthritis and Rheumatic Diseases, Skin Biology and Diseases, Bone Biology and Diseases, Muscle Biology and Diseases, and Musculoskeletal Biology and Diseases—each of which is divided into categories and broad areas of potential research directions. The NIAMS recognizes that overlapping areas exist within each topic, and fully expects many advances to arise serendipitously from research in additional fields as well.

We have also selected four cross-cutting areas, highlighting needs and opportunities that are relevant to many of our research communities. These categories include Health Disparities, Infrastructure, Training and Career Development, and Information Dissemination and Outreach.

I. Health Disparities

Most of the diseases in the NIAMS mission areas are chronic, and many cause life-long pain, disability, or disfigurement. They afflict millions of Americans; cause tremendous human suffering; and cost the U.S. economy billions of dollars in health care and lost productivity. These conditions strike people of all ages, racial and ethnic populations, and economic groups. Many affect women and minorities disproportionately—both in increased numbers and increased disease severity. For example, female systemic lupus erythematosus (SLE) patients outnumber males, nine to one. African American women are three times as likely to get SLE as Caucasian women, and the disease is also more common in Hispanic, Asian, and American Indian women. Rheumatoid arthritis, osteoporosis, and osteoarthritis (in patients over 45 years of age) are also more prevalent among women, whereas certain forms of ankylosing spondylitis occur more frequently in men. SLE risk genes have been identified on the X chromosome, which provides potential evidence for the gender bias in this autoimmune disease.

Skin diseases, as well as some musculoskeletal and rheumatic diseases, frequently create enormous quality-of-life issues. The impact of some of these conditions on patients' lives is significant, and some skin and rheumatic diseases are accompanied by systemic effects and co-morbidities. Conditions such as non-melanoma skin cancer, arthritis, and lower back pain result in billions of dollars of healthcare costs annually for the U.S. federal government. As such, these are important topics for research in molecular pathways and healthcare delivery.

Other factors, such as socioeconomic status, education level, social and cultural issues, and policies and medical practices, create health disparities after disease onset, potentially affecting disease progression and treatment response. These issues, as well as inadequate reimbursement from insurers and government healthcare programs, also present barriers to health services.

The NIH Revitalization Act of 1993 (Public Law 103-43) requires the inclusion of women and minorities in NIH-funded clinical research, unless there is appropriate justification for not including them. Hence, many of these studies could serve as resources for health disparities research. Important, fundamental research approaches include:

  • Establish the current level of health disparities, to allow a rigorous evaluation of progress toward their reduction or elimination.
  • Develop standards for clinical data to define features of health disparities.
  • Identify areas for immediate study, in which health disparities due to minority and/or socioeconomic status are well documented.
  • Use administrative databases (e.g., billing, pharmacy) as a source for health disparities data associated with population groups and medical compliance (e.g., adherence to taking bisphosphonates after hip surgery).
  • Consider socioeconomic factors in the design, data collection, and analysis for clinical research and clinical trials.

The following are some of the important research needs and opportunities in this area:

  • Elucidate ancestry-associated markers to help characterize clinical research participants' racial backgrounds.
  • Investigate genetic, biological, and environmental risk factors among different racial and ethnic populations.
  • Expand research on SLE risk genes on the X-chromosome (e.g., to other autoimmune diseases with female preponderance, and elucidation of associated pathogenic pathways).
  • Pursue research on diseases with significant effects on the health and quality of life of minority populations (e.g., vitamin D insufficiency, vitiligo, and keloids).
  • Conduct behavioral research investigating cultural issues that can influence disease management and outcomes (e.g., risk behaviors and medical compliance), and incorporate findings into patient education strategies, to promote adoption of healthy behaviors.
  • Investigate problems concerning access to care, including health insurance, reimbursement, and socioeconomic factors.
  • Explore the impact of language barriers and cultural health literacy to healthcare delivery.
  • Develop a diverse culturally competent workforce in biomedical research and healthcare, to expand interest and commitment to reducing health disparities.

II. Training and Career Development

The NIAMS is committed to ensuring that a diverse and highly skilled workforce is available to assume leadership roles related to biomedical and behavioral research. The Institute encourages and supports trainees at all levels: predoctoral and postdoctoral training programs and fellowships, mentored career development awards, and grants for newly independent investigators (see box below). The NIAMS participates in a diverse set of NIH-wide training programs and has taken steps to address the specific needs of our research communities by developing new funding opportunities or by modifying existing ones. The NIAMS also partners with professional societies and other organizations to ensure that a comprehensive and complementary portfolio of training opportunities is available. All of these activities aim to fulfill the mandate that Congress gave the Institute when it created the NIAMS; namely, to reduce the burden of illness and to enrich the quality of life for all Americans affected by diseases within our mission.

The scale and complexity of today's biomedical research challenges demand that scientists move beyond their individual disciplines and explore new organizational models for team science. Integrating different areas of research holds the promise of opening up scientific avenues of inquiry and, in the process, may result in new approaches to address increasingly complex questions. To facilitate the exchange of information between investigators, the NIAMS encourages the development of multidisciplinary symposia, seminars, conferences, workshops, and other formal meetings to foster collaborations needed for future research advances. The NIH Conferences and Scientific Meetings (R13/U13) funding opportunity is available to help support such efforts so that investigators can gather to explore a defined subject or area of knowledge. Open, transparent communication among investigators at these venues should help to accelerate the pace of scientific discoveries and facilitate the translation of advances in basic research to clinical application.

The NIAMS also supports NIH policies that formally allow more than one Principal Investigator (PI) on individual research awards. The multi-PI option presents an important opportunity for investigators seeking support for projects or activities that require collaboration. The NIAMS also participates in programs focused on support for new and early stage investigators, a high priority for the NIH. For example, the Pathway to Independence Award (K99/R00) program was developed to increase and maintain the number of new and talented NIH-supported independent investigators. The program is designed to facilitate a timely transition from a mentored postdoctoral research position to a stable independent research position with the NIH or other research support at an earlier stage than is currently the norm.

Training and Career Development Resources

NIAMS Extramural Research and Training Programs

NIAMS Intramural Research Program

NIH Research Training and Research Career Development
(includes information about intramural and extramural training opportunities, diversity supplement programs, fellowships, and loan repayment programs)

Multiple Principal Investigators

New and Early Stage Investigators


The NIAMS employs several clinical training mechanisms. The NIH Mentored Clinical Scientist Development Investigator Award (K08) supports clinicians who need an intensive period of research experience. The NIH Mentored Patient-Oriented Research Career Development Award (K23) is targeted to clinically trained professionals who have the potential to develop into productive, clinical investigators focusing on patient-oriented research. The NIH Midcareer Investigator Award in Patient-Oriented Research (K24) provides protected time for clinicians to conduct patient-oriented research and to act as mentors for beginning clinical investigators.

Through an ongoing assessment of needs and opportunities, the NIAMS has maintained a multi-dimensional approach to training and career development. The Institute's commitment to developing and nurturing a healthy pipeline of biomedical researchers focused on the diseases and disorders within NIAMS mission areas will transform medicine and advance science in the 21st century.

III. Infrastructure

Research infrastructure, such as research consortia, shared facilities, data registries, and biorepositories, are an essential component of modern biomedical research. The sharing of data, ideas, and resources enables unique advantages that may not be otherwise available, and has the potential to dramatically propel science forward. However, infrastructure is expensive and time-consuming to develop and maintain, so it is imperative that researchers stay informed about, and have access to, existing resources. The NIH has made a considerable infrastructure investment through its NIH Roadmap for Medical Research and the National Center for Research Resources (NCRR). NIAMS-funded investigators are encouraged to take advantage of these valuable resources (see box below) that will accelerate progress and make efficient use of Federal research investments. For example, the NIH has established tools available to researchers whose discoveries have clinical applications such as NCRR's Clinical and Translational Science Award (CTSA) program.

Clinical studies, including trials, are a critical part of the biomedical research landscape. Many networks have been started with initial funds from the NIAMS and other NIH Institutes and Centers, as well as from professional and voluntary organizations. When appropriate, these infrastructures are maintained through creative partnerships (e.g., with industry and non-U.S. networks). Management of consecutive or concurrent studies is also often supported by a variety of sponsors. The effectiveness of clinical trials requires early and continuous engagement of community health-care providers and patient populations to help translate research results into clinical practice. Standardized practices and protocols, as well as shared data and samples, may be necessary for certain studies while enhancing the impact of others.

Examples of NIAMS and NIH-funded Research Resources

NIH and NIAMS Clinical Research Resources

NIH-funded Resources (includes biological materials (e.g., adult mesenchymal stem cell processing, biospecimens), genetic analysis tools, and model organisms (e.g., invertebrates, fish, rodents, non-human primates))

Biomedical Technology (includes tools available through the Biomedical Technology Research Centers)

Software and Other Tools for Genome Research

Informatics Support

NIH Molecular Libraries Program for High-Throughput Screening

Mouse Repositories and Databases


Biorepositories and clinical research databases are of great value to scientific communities, but in order to maintain their long-term utility, efforts must be made to develop standards in data quality, collection, storage, nomenclature, and phenotyping, with detailed annotation from medical records. A commitment to data sharing and the attendant challenges—such as ownership and confidentiality—should also be considered in the development of informed consent documents and network management.

Broad areas include:

Collaborative research

  • Expand and intensify research collaborations and communication between disease-focused research centers, medical research centers, health-care providers, and patients.
  • Expand the use of multi- and cross-disciplinary research teams.
  • Coordinate teams of researchers to develop and evaluate biomaterials.
  • Expand the use of clinical trials consortia.
  • Develop technologies and mechanisms to foster multi-site collaborations.

Shared facilities and standardized resources

  • Centralize stem cell resources to standardize nomenclature and protocol development.
  • Encourage the development of shared core resources including state-of-the-art technologies and instrumentation.
  • Expand the development of advanced biomedical imaging technology.
  • Standardize imaging protocols.

Model systems

  • Facilitate the development and characterization of animal models for diseases and disorders: optimize genetic background, standardize outcome measures, expand phenotyping resources, and increase the availability of models and sharing of data.
  • Expand the use of other model systems, such as zebrafish and invertebrates, where appropriate and advantageous.
  • Develop large-animal models for preclinical studies to assess long-term function outcomes.
  • Further develop and characterize human cell and tissue models for studies of disease pathophysiology and regenerative medicine. Such models may include iPS cells or other multi-/pluri-potential cell lines from individuals with genetic disorders as well as normal subjects.
  • Further utilize human cell and tissue model systems in high throughput screens for potential therapeutic agents.
  • Develop 3-D human tissue models for basic and translational research.
  • Facilitate bioinformatics efforts for the processing of large amounts of data required for model development.
  • To support the development of rigorous model systems, develop standards for collecting and reporting results from gene expression studies.
  • Build consensus on a set of standards for systems biology models, so that models can be tested across different platforms.
  • Create a database of models to be tested and validated by the scientific community.

Data registries and biorepositories

  • Characterize resources and information and increase their availability and utilization by investigators; network existing registries and repositories and link them to data sets.
  • Expand molecular infrastructure, including cell and molecular libraries, gene and protein expression profile databases and analysis tools, and clinical databases.
  • Establish coordinated consortium efforts to create the necessary infrastructure to enhance cooperation among diverse partners: Ultimately, provide the scientific community with a large enough dataset and biorepository to facilitate studies to identify and validate novel markers of drug response.

Examples of NIAMS and NIH-funded Resources for Research Translation

NIAMS Centers of Research Translation

NIAMS Research Core Centers

NIAMS Multidisciplinary Clinical Research Centers

Clinical and Translational Science Awards (CTSAs)

Collaboration, Education, and Test Translation Program for Rare Genetic Diseases

National Gene Vector Biorepository and Coordinating Center

NIH Rapid Access to Interventional Development

IV. Information Dissemination

Disseminating information about research progress continues to be an essential component of the NIAMS mission. The NIAMS is committed to communicating research advances to all segments of the public. The driving force behind NIAMS-funded research is the potential to improve the lives of those who are affected by bone, joint, muscle, or skin diseases. Therefore, the Institute is committed to working closely with grantee institutions to disseminate research findings to varied audiences via multiple venues. NIAMS long-range plans include

  • continuing its efforts in information dissemination by providing easy access to current, evidence-based, and audience-appropriate health information (see box below);
  • engaging the public and encouraging participation and input in NIAMS and NIH activities;
  • raising awareness of NIAMS-funded research and opportunities;
  • increasing visibility of the NIAMS as the leading resource for research-based information on diseases and conditions of the bones, joints, muscles, and skin; and
  • expanding understanding among scientists and students about careers and training opportunities in biomedical research fields under the NIAMS mission, particularly in underrepresented communities.

The NIAMS relies on a coalition of more than 65 professional and voluntary health organizations to share research advances and related developments, and to foster dialogue on the future path of NIAMS-funded research. The NIAMS Coalition plays a vital role as a liaison among the researchers that the Institute supports, the patients who benefit from the Institute's research investments, the Congress, and the American public.

The NIAMS supports and operates the NIAMS Information Clearinghouse and the NIH Osteoporosis and Related Bone Diseases~National Resource Center. Both distribute health education materials to patients, health professionals, researchers and scientists, voluntary and professional organizations, and the media (see and box below). The NIAMS Information Clearinghouse provides materials on diseases and conditions of bones, joints, muscles, and skin. Health information in English, Spanish, and Chinese is available in a variety of formats, including an expanding library of audio publications that can be downloaded from the NIAMS Web site. The National Resource Center is a partnership effort led by the NIAMS with support from the National Institute on Aging, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the NIH Office of Research on Women's Health, and the HHS Office on Women's Health. It provides information on metabolic bone diseases, including osteoporosis, Paget's disease of the bone, and osteogenesis imperfecta. Resources include an interactive Web site for assessing bone health and materials derived from the publication, Bone Health and Osteoporosis: A Report of the Surgeon General.

To broaden our outreach to underrepresented groups, the NIAMS has taken a leading role in establishing the Trans-NIH American Indian and Alaska Native Health Communications and Information Work Group, a collaboration that represents 16 NIH Institutes and Centers. The Work Group has developed a partnership with the Indian Health Service's National Community Health Representative Program, a network of 1600 Tribal employees who serve as lay health educators and patient liaisons in Native communities nationwide.

The Institute also remains committed to its Health Partnership Program, and the program's Community Health Center, which addresses health disparities in arthritis and other rheumatic diseases, and provides health education in Washington, D.C., metro area minority communities. Through ongoing research with underrepresented patients affected by arthritis and other rheumatic diseases, program researchers study health disparities and their causes. The scientists also explore directions for improving the health status and outcomes of minority communities. Additionally, dozens of our intramural clinical fellows are benefiting from a unique community-based learning experience in rheumatic diseases at the Community Health Center. The NIAMS will continue to collaborate with the program's partners by providing health education materials, staffing local health fairs, and obtaining partners' input on the development of culturally appropriate materials.

In FY 2010-2014, the NIAMS will continue its National Multicultural Outreach Initiative, a project to ensure that research results and health information reach diverse populations. Plans for the Initiative include

  • improving access to research-based and culturally relevant health information for minority and underserved populations;
  • emphasizing that research is the foundation for progress in achieving better bone, joint, muscle, and skin health; and
  • involving voluntary and professional organizations within the NIAMS Coalition in multicultural outreach.

Information Dissemination Resources

What sort of publications does the NIAMS offer?
The NIAMS develops health information materials for patients, health-care providers, and the public. Some are in an easy-to-read format; others are available as audio publications. The Institute is also adapting some publications for Spanish or Chinese speakers. The NIAMS has CD-ROMs that contain print-friendly versions of many of its materials, which health professionals and patient organizations can print and distribute as needed

How do I order publications from the NIAMS?
Please visit the NIAMS Web site ( or call 877-226-4267 (TTY 301-565-2966) (toll free call).

How can I stay informed about NIAMS activities?
Each month, the NIAMS produces an electronic digest to update those interested in the latest scientific news and resources on diseases of the bones, joints, muscles, and skin. Please visit to subscribe to the NIAMS Update.

Where can I find answers to other questions about the NIAMS, its research, or its publications?
Please visit


Disease- and Tissue-specific Topics

I. Arthritis and Rheumatic Diseases

The NIAMS Arthritis and Rheumatic Diseases programs cover basic, translational, and clinical research in a number of autoimmune and arthritis-related chronic disorders. These include, but are not limited to, the adult diseases of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE, or lupus), scleroderma, and Sjögren's syndrome. Others include pediatric diseases, such as juvenile idiopathic arthritis, periodic fever syndromes, and juvenile lupus, which generally have a more severe onset than the adult form of lupus. The NIAMS Arthritis and Rheumatic Diseases programs also support studies focused on the basic biology of autoimmunity and inflammation, to better understand the molecular mechanisms underlying these processes, with the goal of finding ways to interrupt them and improve patient outcomes. The Institute is pursuing opportunities in genetics and genomics research, clinical trial design, pain, and biopsychosocial aspects of diseases in this portfolio, as well as identification of risk factors for these disorders.

Arthritis and Rheumatic Diseases: Genetics and Genomics

Rheumatologists have long recognized the incidence of many rheumatic diseases within families and certain ethnic populations, pointing to some role of genetic risk. Scientists' perseverance in gathering biospecimens and clinical histories from patients and their relatives, along with the explosion of knowledge and techniques in genetics and genomics, have opened new avenues of research. These findings will lead to improved understanding of what causes disease and how it progresses and, ultimately, the development of better tools for diagnosis, prognosis, prevention, and personalized approaches to medicine.

1. Discovery of disease genes and gene products

Genome-wide association studies have transformed the discovery of gene regions, or loci, related to disease risk, through unbiased analyses of patients with a disease compared to controls without it. Association and linkage association studies have yielded important insights into complex rheumatic disorders, such as lupus (see box below), rheumatoid arthritis, and ankylosing spondylitis. This research has also revealed common genetic factors contributing to other autoimmune diseases, as well as co-morbidities. However, genome-wide association approaches can only identify regions that harbor risk genes, requiring follow-up studies to discover the precise, disease-causing gene variants, or single nucleotide polymorphisms (SNPs). In addition, the SNPs found through genome-wide association studies describe only a small fraction of inherited disease risk. Hence, alternative genomic approaches should be considered, in order to capture and characterize additional genetic variants.

Advances in lupus genetics: Several research advances have identified susceptibility genes for lupus, contributing to a new understanding of risk for this disease. Researchers have employed genome-wide association studies, linkage analysis, and direct sequencing in large, case-controlled lupus studies. Several of the findings have been replicated in studies with distinct racial or ethnic populations. Many previously identified SNPs associated with immune regulation gene loci, such as histocompatibility molecules, STAT4, and interferon regulatory factor 5, have now been confirmed1. Newly discovered SNPs occur in genes encoding molecules involved in vascular cell adhesion2, clearance of immune complexes3, and immune cell development and maturation. Disease-associated alterations in the protein products of these genes may contribute to vascular complications, persistence of inflammatory stimuli, and impaired tolerance mechanisms, leading to autoimmunity. In addition, the STAT4 gene, but not other lupus risk genes, has been associated with the most severe forms of disease4 that manifest lupus nephritis. Recent evidence from mouse5 and human observational studies6 suggests that gene dosage effects from X-chromosomes may help explain the preponderance of lupus in women.


1 SLEGEN, et al., Nat. Genet. 2008, PMID: 18204446
2 Nath SK, et al., Nat. Genet. 2008, PMID: 18204448
3 Edberg, JC, et al., Hum. Mol. Genet. 2008, PMID: 18182444
4 Taylor KE, et al., PLoS Genet. 2008, PMID: 18516230
5 Smith-Bouvier DL, et al., J. Exp. Med. 2008, PMID: 18443225
6 Scofield RH, et al., Arthritis Rheum. 2008, PMID 18668569


Broad areas of potential research directions include:

  • Use genome-wide association studies to find genetic loci that confer risk for disease and conduct follow-up studies for detailed mapping of loci that are putatively associated with complex traits.
  • Apply next-generation sequencing technologies and other novel approaches to identify disease-causing variants, including common, rare, and other structural variants.
  • Enhance the use of well-characterized, family-based cohorts to explain heritable traits, using combined linkage and association analyses.
  • Extend association and linkage analyses to studies with specific ethnic groups and circumscribed populations.
  • Apply high-throughput methods of transcriptome and proteome analyses to assess the impact of genetic mutations on gene expression patterns.
  • Explore epigenomic variation and its possible association with disease.
  • Mine whole-genome data to discern disease and phenotype-specific genes and their products, as well as such genes shared by various autoimmune diseases.
  • Enhance the use of large, well-characterized (clinically, serologically, and immunologically) collections of cases and matched controls, especially existing cohorts, to enable genetic and epidemiological studies.
2. From genetic variation to biological mechanisms of disease

Current research tools enable scientists to associate gene expression with physiological effects. In addition to providing information about genetic risk for disease, genome-wide association studies identify pathogenic pathways and therapeutic targets. Epigenomics, gene-environment interactions, chromatin structure, copy number variants, and microRNAs may have roles in disease risk and pathogenesis and may also contribute to co-morbidities.

Broad areas of potential research directions include:

  • Integrate gene expression profiling through genotypic and clinical data collection and analysis from large cohorts and explore network-based or similar approaches to elucidate the complexity of disease traits.
  • Translate complex genetic analyses in mice to humans, making use of positionally cloned quantitative trait loci for detailed phenotyping to study mechanisms of action of human disease genes.
  • Characterize the functional effects of genetic variants on disease susceptibility and phenotypes using robust in vitro and in vivo systems, including studies of single genes, multiple genes, gene-gene interactions, and gene-environment interactions.
  • Elucidate the role of epigenetic mechanisms in the onset and progression of rheumatic diseases.
  • Conduct exploratory, discovery-driven experiments with genomics and proteomics in scleroderma, myositis, and polychondritis, using patient samples linked to robust clinical data and biostatistical analysis.
  • Explore how human genetic mutations affect innate immunity that is associated with autoimmune and autoinflammatory diseases. Similarly, explore the interaction between genes associated with immunodeficiency and autoimmune diseases in disease susceptibility (see the next segment, Mechanisms of Disease, Immune and inflammatory mechanisms, for more information).
3. Pharmacogenomics and personalized medicine

The rapidly progressing field of pharmacogenomics offers powerful tools to study the influence of genomic variations on drug response by correlating gene expression or SNPs with drug efficacy or toxicity. The application of pharmacogenomic approaches to therapies used in arthritis and rheumatic diseases holds great promise for "personalized medicine," in which drugs and drug combinations can be tailored to each individual's unique genetic makeup.

Broad areas of potential research directions include:

  • Perform gene expression and SNP analyses to identify genetic and genomic variations that produce inter-individual differences in drug response—in both efficacy and toxicity.
  • Elucidate the mechanisms underlying differences in treatment responses and apply the results to the identification of novel pathways and therapeutic targets.
  • Investigate the function of noncoding RNAs (including microRNAs) and genomic repeat elements (e.g., transposable elements) in the pathogenesis of autoimmune diseases.
  • Develop and validate clinically useful models that can effectively discriminate responders and non-responders to pharmacologic and biological interventions in rheumatic diseases, in order to direct therapies to the appropriate subsets of patients.

Arthritis and Rheumatic Diseases: Mechanisms of Disease

1. Immune and inflammatory mechanisms

Increased knowledge of autoimmunity and basic functioning of the immune system has advanced our understanding of arthritis and other rheumatic diseases. Two arms of the immune system—the innate and adaptive immune systems—coexist in a delicate balance. Normally, the body's surveillance for infection and tissue injury requires that immune cells interact with each other and with cells of target organs, such as bone, muscle, skin, and joints. However, dysfunction in this regulation may lead to autoimmune disease, such as in rheumatoid arthritis, when joint inflammation caused by the immune system's attack on abnormal synovial tissue. Better understanding of interactions between the immune system and various tissues in normal and pathological conditions will lay the groundwork for future therapies for autoimmune diseases.

A. Innate immunity

The innate immune system is the body's first line of defense against invading pathogens, launching an attack on these antigens with a rapid and non-specific response. The innate immune system can distinguish microbes ("non-self") from the human body's own molecules ("self") by recognizing conserved structures called pathogen-associated molecular patterns (PAMPs). Proteins called toll-like receptors (TLRs) recognize PAMPs—from both self and non-self sources—and trigger a resulting inflammatory response (see box below). In addition, NOD-like receptors (NLR) similarly recognize self- and non-self molecules that are produced inside a cell. Multi-protein complexes called "inflammasomes" act as launching pads, in concert with TLR and NLR signaling, to set in motion the inflammatory process.

Broad areas of potential research directions include:

  • Study the role of innate immune system components—such as TLRs, inflammasomes, and associated signaling pathways—on the initiation and propagation of autoimmune diseases.
  • Expand understanding of the cross-regulation between components of the innate and adaptive immune systems in inflammation and rheumatic diseases (e.g., TLR-induced maturation and activation of plasmacytoid dendritic cells to produce type I interferon; direct regulation and activation of TLR-expressing T and B cells in response to TLR ligands).
  • Investigate the oral and gut microbiomes as potential triggers for rheumatic autoimmune diseases.
  • Study the involvement of a wide range of hematopoietic and other cell types in rheumatic diseases. Examples include macrophages, monocytes, neutrophils, dendritic cells, natural killer cells, mast cells, basophils, eosinophils, fibroblasts, and synoviocytes.
  • Understand the contribution of dysregulated cellular processes (e.g., programmed cell death, necrosis, autophagy) in the cause and progression of autoimmune disorders.

Innate immune system involvement in lupus: Studies in mice with a lupus-like disease have revealed that the innate immune system's TLRs, which were previously thought to only recognize pathogenic viruses and bacteria, could also react to the body's own molecules. Researchers found that TLR7 binds to RNA and TLR9 binds to DNA, and that the source of that genetic material may be from pathogens or mammals. Eliminating TLR7 in these lupus-prone mice resulted in no anti-RNA antibodies and less severe disease. The lupus-prone mice without TLR9 lacked anti-DNA antibodies but, surprisingly, had worse disease. Lupus is often characterized by the presence of autoantibodies to the patient's own genetic material. These findings provide critical information for the development of therapies that may target the innate immune system as well as the production of damaging autoantibodies.

For further information, see:

Two Proteins Found to Have Unexpected Effects on Lupus


B. Adaptive immunity

In contrast to the innate immune system, the adaptive immune system provides more specific, targeted, and sustained responses. Successful adaptive immunity against a broad range of pathogens depends on the body's ability to produce randomly generated, diverse receptors on the surface of lymphocytes. Because of the enormous number of antigens that the body routinely encounters and their potential similarity to self components, the adaptive immune system is at risk of producing self-reactive (autoreactive) cells that can trigger autoimmunity. Immune tolerance addresses this problem by either removing autoreactive cells from the system or by diminishing their reactivity enough to prevent disease. Autoimmune disease can occur when there is a breach or dysregulation in this process of immune tolerance. Thus, a better understanding of the mechanisms of adaptive immunity and autoimmune diseases may help in the development of antigen-specific therapies that leave protective, global immune function intact.

T helper cell subsets: Studies in recent years have identified a number of T helper cell (Th) subsets that initiate specific types of immune responses to different classes of microbes or other triggers, and are important for launching attacks against pathogens and autoimmune reactions. Researchers have found that one Th subset, Th17, releases messenger molecules, such as interleukins 17, 21, and 22, that start a cascade of inflammatory events. Biologic therapies that block activation of Th17 cells are effective in the treatment of psoriasis, which can develop into psoriatic arthritis. In particular, interleukin 17 is being targeted in clinical trials for rheumatoid arthritis1 and ankylosing spondylitis patients.

The effects of Th17 and other pro-inflammatory cells are balanced by another Th subset, Tregs, which dampen inflammation. Additional studies have revealed ways that the body might inactivate Tregs. The plasticity of immune system components (such as the ability of Tregs to become Th17 cells, and, potentially, the reverse2) has shifted some attention in our understanding of disease pathogenesis and treatment from cellular and molecular targets to pathways, regulation, epigenomics, and system imbalances.


1 Garber, K, Nat. Biotechnol. 2009,
2 Wei G, et al., Immunity 2009, PMID: 19144320


Broad areas of potential research directions include:

  • Clarify the role of the major histocompatibility complex and antigen-presenting cells in autoimmunity.
  • Further define the role of regulatory T cells (T regs) and cytokines in immune responses and autoimmune diseases.
  • Expand understanding of autoantigen expression in rheumatic diseases, including the role of metabolic and other changes in tissue or organ environments that lead to autoantigen production.
  • Define and characterize mechanisms that control tolerance to self and the production of autoantibodies.
  • Investigate the established roles of B cells in autoimmune diseases (autoantibody production), as well as their more newly elaborated functions (antigen presentation and co-stimulation during initiation of immune responses, and the release of inflammatory and immunomodulatory cytokines).
  • Elucidate the mechanisms by which sex hormones and sex-specific gene products influence immune functions, in an effort to understand why autoimmunity is so much more common in women.
C. Inflammation and inflammatory mediators

Chronic inflammation is a characteristic of many autoimmune diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory myopathies, and lupus. Inflammation causes swelling, pain, and damage to organs. Research advances concerning the molecular and cellular contributors to this condition have provided critical insights into the potential causes of inflammation (see box above). Understanding both triggers and amplifiers of inflammation will help researchers design targeted therapies.

Broad areas of potential research directions include:

  • Explore the role of specific cytokines, chemokines, eicosanoid (and other lipid mediators), proteases (including the neutral proteases from mast cells), inhibitors of proteases, as well as receptors for these molecules in the autoimmune and inflammatory components of rheumatic diseases.
  • Conduct further research in the development and biological functions of T cell subsets, as related to the inflammatory process in rheumatic diseases (e.g., Th17 cells as a dominant contributor of the inflammation seen in rheumatoid arthritis, the role of T regs in ameliorating inflammation).
  • Identify and characterize molecular mechanisms that either resolve or dampen inflammation (e.g., anti-inflammatory cytokines, chemokine/chemokine receptors and "decoys," lipid-derived mediators, leukocyte apoptosis).
  • Investigate the influence of immune cell trafficking on disease mechanisms, including the identification of key players in leukocyte migration from the vasculature to surrounding tissues (extravasation), and examination of the roles of the adhesion molecules and chemoattractants that mediate cell trafficking.
  • Study potential environmental triggers of pathogenic pathways and inflammation, such as infection (as in Lyme disease), smoking, diet, vascular components, and inflammation-associated factors.
2. Target organ damage

The manifestations of rheumatic diseases are diverse and can affect many organs and organ systems, including the joints, skin, and internal organs, such as the kidneys, heart, lungs, blood vessels, and the brain. Although immune dysregulation plays a major role in these diseases, structure and function of target organs such as the vasculature may contribute significantly to the development of tissue damage and clinical disease. A better understanding of mechanisms of tissue damage may suggest how to modify these processes and approaches to minimize or prevent some of the most serious complications of autoimmune disease.

Broad areas of potential research directions include:

  • Explore the interrelationships between immune response components (both innate and adaptive) and target tissues or organs (e.g., synovium in rheumatoid arthritis, kidney in lupus) in normal and pathological conditions.
  • Characterize and understand how autoantibodies cause disease.
  • Elucidate the effector mechanisms of tissue damage (e.g., complement, cytokines, and immune complexes).
  • Investigate how organ responses sustain inflammatory disease.
  • Identify associations between chronic inflammation and the initiation and progression of atherosclerosis.
  • Understand the roles of vessels and vascular endothelium in the pathogenesis of inflammatory rheumatic diseases.
  • Discover and characterize the links between immune dysfunction and nervous system involvement in rheumatoid arthritis, lupus, scleroderma, and other rheumatic diseases.
3. Pain

Chronic pain can be an important aspect of many of the diseases within the NIAMS portfolio. The contribution of chronic joint and musculoskeletal pain to patient suffering and burden, particularly when worsened by acute conditions, is likely to increase substantially as the U.S. population ages. Many clinically important aspects of pain are not adequately understood. While there have been many developments in the understanding of pain and how it is treated, these have not been easily translated into interventions for chronic pain, which is a serious public health problem.

Broad areas of potential research directions include:

  • Investigate interactions among the peripheral nervous system, the central nervous system, and the inflammatory system, which contribute collectively to the development of chronic pain.
  • Characterize reversible and permanent biochemical and anatomic changes that cause, or are caused by, chronic pain.
  • Identify a set of biological, behavioral, genetic, epigenetic, cognitive, psychological, and social factors (e.g., the "pain fingerprint") that makes an individual susceptible to chronic pain, the transitions from acute to chronic pain, and that from pediatric to adult pain.
  • Study the heterogeneity and epidemiology of pain syndromes to understand their genetic risk factors, the mechanisms by which they develop, and variations in phenotype.
  • Generate tools for the diagnosis of chronic pain conditions, animal models of chronic pain, and behavioral measures of pain.
  • Develop novel therapeutic approaches to treat chronic pain conditions that encourage the development of analgesic drugs, personalized therapeutics, and biobehavioral interventions.

Arthritis and Rheumatic Diseases: Preclinical and Translational Research

Unraveling the complexity of rheumatic diseases requires an understanding of how disease causation and progression are integrated, so effective and targeted therapies can be developed. Much of this research is conducted in model systems, which leads to further refinement of therapeutic approaches and design before human testing.

Recent progress in developing molecular and genetic tools for basic research has facilitated disease-specific investigations. These studies aim to advance knowledge of underlying mechanisms and facilitate the development of therapies that are likely to be adopted into clinical practice. In an exemplary translational research study, scientists analyzed a cluster of 12 genes from patients with systemic onset juvenile idiopathic arthritis (SoJIA) and determined that the gene expression profile was distinct from the profiles of other inflammatory conditions, such as lupus or acute infections. As a result of disease-targeted studies like this, a genetic signature has been developed for the early detection of SoJIA. In addition, the work has guided the clinical testing of interleukin-1 receptor blockade for the treatment of SoJIA, which may translate effectively to clinical practice and lead to a strategy to prevent the disease's progression.

1. Model systems

Model systems aim to define disease mechanisms as well as design and test approaches to prevent disease progression. Animal models offer some of the best systems for detailed phenotyping of various diseases and conditions, so scientists can identify and study how human disease genes work. Current mouse models focus on immune cell function and recapitulate aspects of human diseases, such as rheumatoid arthritis and lupus, which provides important information about pathogenic and therapeutic pathways and their interactions.

Given the complexity of immune responses, etiologic and mechanistic questions about disease are difficult to answer. By integrating large amounts of research data into a dynamic model, systems biology approaches can be used to better understand the interrelationships between immune system components over time and their regulation (see Model development under Model Systems and Therapy Development in the Skin Biology and Diseases section, for more information on systems biology).

Broad areas of potential research directions include:

  • Develop animal models for functional and mechanistic studies of pathogenic pathways identified by genome-wide association studies and other human genetics research.
  • Create new animal models and use existing transgenic animals, and other genetically modified animal models, to study the immune and inflammatory mechanisms of arthritis and rheumatic diseases.
  • Combine animal models of human rheumatic diseases with systems biology approaches, to identify critical cellular and molecular pathways involved in disease causation, and to facilitate the identification of therapeutic targets.
  • Develop animal models to better understand the differences between autoimmune mechanisms and those that cause target organ damage.
2. Therapy development

Advances in immunology, molecular biology, and genetics are yielding an emerging set of therapies for arthritis and rheumatic diseases. While new treatments for rheumatoid arthritis and lupus are being tested by the private sector, the goal of NIAMS-supported research is to ensure a continuous supply of new targets for intervention, to understand the mechanisms of action of new drugs, and to develop adequate trial methodologies.

Broad areas of potential research directions include:

  • Build on the successful treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs, particularly early interventions to prevent progression to severe disease and tissue damage, toward the development of therapies for lupus, scleroderma, ankylosing spondylitis, and other spondyloarthropathies.
  • Create therapeutic strategies to target immune dysregulation in arthritis and rheumatic diseases.
  • Explore joint-tissue modeling pathways to better understand pathophysiology and etiology of rheumatoid arthritis, and to identify new therapeutic targets.
  • Foster pharmacogenetics and pharmacogenomics research to investigate the genetic basis of individual therapeutic response using genome-wide association studies in large patient cohorts.
  • Explore the integration of genetic and genomic analyses with the molecular diagnosis of disease in clinical care.
  • Explore gene-based therapies using gene silencing (microRNAs or small interfering RNAs) and overexpression approaches to treat or prevent disease.
3. Biomarkers

The goal of biomarker research is to use modern approaches to discover and qualify biomarkers for the diagnosis, prognosis, and evaluation of therapies. In general, biomarkers are measured by changes in biochemical factors or genetic markers in blood, body fluids, or tissues. For many disorders, a battery of biomarkers rather than a single biomarker may provide the most clinically useful information.

Broad areas of potential research directions include:

  • Define and test algorithms in an appropriate population that integrate different sets of biomarker data (e.g., genetic, imaging, serologic, patient-reported) with sufficient power to facilitate personalized clinical decision-making regarding prognosis, treatment, and prevention.
  • Develop biomarkers to predict disease preclinically, using combinations of genetic predisposition, autoantibodies, metabolites, and other phenotypic characteristics.
  • Expand the use of autoantibodies as models for biomarker development to identify disease subtypes, and to track disease progression and therapeutic response.
  • Generate sensitive and reliable analytical methods coupled with assays that can detect multiple biomarkers ("multiplex") in patient and control samples, to evaluate the complex systemic changes seen in rheumatic diseases.
  • Create resources needed to move promising biomarkers from the bench to the clinic using state-of-the-art statistical, analytical, and computational methods.
  • Develop validated and standardized outcome measures to enable a better assessment of biomarkers and the success of interventions.
  • Define disease heterogeneity at the molecular level by applying functional genetic and genomic information—as well as environmental and social factors—to the refinement of phenotypes and subcategories of complex rheumatic diseases.
  • Link developments in genetics, genomics, proteomics, bioinformatics, and systems biology to clinically relevant issues, particularly the prediction, prevention, and monitoring of rheumatic diseases. Develop genetic profiling models for the prediction of disease risk, progression, and prognosis, using measures of clinical validity that can accurately assess the net benefit of a genetic testing strategy.
  • Evaluate reliable and clinically useful biomarkers of disease onset, progression, and prognosis in children and adults.
4. Imaging

Imaging early or late changes of disease in target organs is increasingly important for characterizing disease status and determining responses to therapies. Advanced imaging technologies are providing insights into anatomic changes in disease states. Magnetic resonance imaging (MRI) has detected structural pathology in rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

Broad areas of potential research directions include:

  • Use and enhance intravital microscopy and improved fluorophores to gain new insights into cellular interactions and potential mechanisms of disease.
  • Enhance detection and quantitative measurements of structural pathology and inflammatory activity with MRI, ultrasound, and positron emission tomography (PET), for assessing rheumatoid arthritis.
  • Investigate the use of non-invasive imaging technologies in functional studies of disease prognosis and progression, potentially in association with biomarker qualification.
  • Develop novel imaging technologies to enable the analysis of soft tissues, including heart, blood vessels, kidney and the brain, to assess end-organ damage in rheumatic diseases.
  • Develop safer imaging approaches for clinical practice.

Arthritis and Rheumatic Diseases: Clinical Research

The complexity of rheumatic diseases, and the diverse presentation and progression of many of these illnesses across patient populations, creates significant challenges in the diagnosis and management of these conditions. Clinical characterization of disease subtypes is critical to the assessment of epidemiological data and the efficient design of clinical trials. The NIAMS supports clinical research, ranging from epidemiological studies to observational studies to clinical trials, designed to further our understanding of these diseases and to develop effective therapies.

1. Epidemiology and health services research

The incidence, morbidity, and mortality of rheumatic diseases are important foci for epidemiological research, particularly for studying complex, systemic, autoimmune diseases and co-morbidities. Health services delivery for patients with rheumatic diseases is an important example of how illnesses with low mortality can still have significant physical and quality-of-life effects.

Broad areas of potential research directions include:

  • Define and test preclinical strategies to understand disease pathways in humans to facilitate individualized screening and risk detection to prevent or treat early disease.
  • Combine analysis of the natural history of disease with population-based epidemiological studies to determine the prevalence of diseases and associated co-morbidities (e.g., cardiovascular disease).
  • Research the effects of patient-health care system interactions in disease outcomes.
  • Conduct research on environmental exposures that may contribute to the development of rheumatic diseases.
  • Focus prevention studies on risk-factor identification and reduction strategies, and conduct early intervention trials to prevent onset or progression of disease or tissue injury.
  • Explore the interactions between rheumatic diseases and common co-morbid conditions, such as atherosclerosis, to design effective risk management strategies, appropriate monitoring, and evidence-based early interventions.
  • Develop computer models to assess the influence of prevention and treatment strategies on outcomes and cost-effectiveness in common chronic diseases (e.g., rheumatoid arthritis).
2. Clinical trials

Many rheumatic diseases do not respond to treatment, particularly due to the diverse presentation and progression of these illnesses within a patient population, along with the complex interactions of biological pathways. Therapies that appear to be promising through preclinical modeling and testing require clinical testing in defined patient populations, or cohorts, and creative approaches to design the assessment of health outcomes.

Broad areas of potential research directions include:

  • Establish the role (qualification) of biomarkers to diagnose, predict, or monitor disease progression and therapeutic response (efficacy and safety).
  • Employ large, systems approaches to disease modeling populated by well-defined phenotypes and qualified biomarkers, towards the development of more efficient clinical trial designs (by predicting cohort size) and more informed clinical decision-making (cost-effectiveness, potential toxicity vs. prevention, quality-of-life impact over time).
  • Test drugs approved for conditions with similar pathogenic pathways in rheumatic diseases (e.g., drugs approved for rheumatoid arthritis in lupus, ankylosing spondylitis, or psoriatic arthritis).
  • Conduct proof-of-concept and bridging studies of approved and available therapeutics, to address clinically important questions in rheumatic diseases.
  • Investigate specific treatments for pediatric rheumatic diseases.
  • Study the pharmacogenomics of responders and non-responders to pharmacologic and biological interventions in rheumatic diseases, in order to direct therapies to the appropriate subsets of patients.
  • Develop and test mechanism-based treatments (individual or combinations of drugs and biologics), strategies and/or models of rheumatic diseases that seek to prevent onset, induce remission (on or off medication), predict and address disease flare, and inform ongoing personalized treatments.
  • Conduct clinical trials related to the cause and treatment of system-specific pain.
  • Examine the comparative effectiveness of therapies, and use combination therapy approaches for the treatment of rheumatic disease.
  • Explore alternative clinical trial designs for rare rheumatic diseases. Examples include active comparators rather than placebo controls, examples from cancer trials that have small cohorts, reassessed clinical research endpoints, and long-term clinical response.
  • Expand the involvement of clinical practice physicians in community settings in large-scale trials.

Arthritis and Rheumatic Diseases: Behavioral and Biopsychosocial Research

Understanding the etiology, pathogenesis, and outcomes of rheumatic diseases, and developing effective strategies for their prevention and treatment, requires a multifaceted approach. These endeavors necessitate collaborative research efforts that integrate approaches and perspectives from multiple disciplines.

Biomedical research in the rheumatic diseases continues to yield important discoveries regarding genetic, immunologic, and other biological factors in these conditions. Behavioral and social science research are contributing important epidemiologic information and approaches to managing the distressing symptoms of these disorders (see box below). However, studies integrating behavioral, basic biomedical, and clinical rheumatology perspectives have been extremely limited to date. The potential of the behavioral and social sciences and a biopsychosocial approach to advance research in the rheumatic diseases has not been fully realized. Interdisciplinary investigations that integrate behavioral and biomedical sciences will likely enhance treatment of these diseases, reduce disability, and may shed light on the complex mechanisms involved in disease processes.

Patient-reported outcomes: Patient-reported outcomes (PRO) instruments, which have traditionally been used for disease-specific, quality-of-life assessments, are very popular among patients. However, patient concerns and their rankings may be very different from the outcomes that physicians seek. The NIH Roadmap's Patient-Reported Outcomes Measurement Information System (PROMIS) initiative is creating a psychometrically-robust PRO instrument to gather information on many health-related concerns, such as pain, fatigue, and physical functioning, across a wide range of disorders. This information will be used to classify symptoms, and to measure changes over time and in response to treatment. The component questions of the PROMIS instrument undergo rigorous testing in culturally and ethnically diverse populations, with a particular focus on the individual use of language to describe PROs. They are being designed for future use in a variety of venues (for example, in clinical trials or physician visits).

For further information, see:

NIH Roadmap for Medical Research: Clinical outcomes—PROMIS (

PROMIS Web site (


Broad areas of potential research directions include:

1. Biobehavioral
  • Define genetic and environmental influences on behaviors relevant to health and disease.
  • Investigate the central nervous system-endocrine-immune interactions that contribute to disease mechanisms and clinical symptoms.
  • Explore cognition and cognitive dysfunction in rheumatic diseases, including the use of brain imaging and assessment of relationships between cognition, mood disturbance, and disease activity.
  • Use biopsychosocial approaches to understand gender, ethnic, and socioeconomic differences in clinical disease, symptom perception and management, and interactions with health-care systems.
  • Generate theoretical models for the potential influence of stress on disease course and presentation (e.g., symptom flares). Research the influence of stress management techniques and interventions on illness, and study potential mechanisms of stress-illness effects.
  • Study fatigue in the rheumatic diseases, focusing on epidemiological issues, potential mechanisms, prevention, and treatment.
  • Investigate sleep disturbances and their relationship to disease process, symptoms, and disability in rheumatic diseases.
  • Address issues in pediatric rheumatology, including pain, psychosocial adjustment, physical functioning, and intervention.
  • Develop animal models to elucidate biobehavioral mechanisms in rheumatic diseases.
2. Therapies
  • Conduct studies on the management of chronic symptoms, such as itch, fatigue, and pain.
  • Investigate placebo responses to pain and treatment, and the impact of catastrophizing and individual pain experiences in disease management and treatment response.
  • Explore integrative and complementary therapies, such as biofeedback, relaxation, mind-body interactions, cognitive behavioral therapy, and exercise.
  • Investigate the role of non-pharmacological treatments and combined individual, group, and technology-based interventions for the self-management and improvement of health-related behaviors.
3. Psychosocial
  • Study the biological, social, and behavioral interactions as they relate to disease onset, progression, and outcomes.
  • Define the effect of systemic and societal influences on disease progression, treatment response, quality of life, and other patient-reported outcomes in rheumatic diseases.
  • Study the variability in patient outcomes, related to differences in behavior, gender, ethnicity, family environment, prior trauma, education, physiology, or a combination of factors.
  • Explore behavioral factors that influence patient interactions with providers, and how this experience affects treatment response and long-term outcomes.
  • Examine psychosocial prevention and intervention models from other disorders (e.g., diabetes, AIDS), for the promotion of healthy behaviors and management strategies for people/patients with rheumatic diseases.

II. Skin Biology and Diseases

The Skin Biology and Diseases programs at the NIAMS cover basic, translational, and clinical research in skin. This includes work on the molecular, cellular, and developmental biology of skin, the study of skin as an immune organ, wound healing, and autoimmune, inflammatory, and genetic diseases of skin. Fundamental research findings in this area contribute to the development of tools for clinical diagnosis, therapeutics, and disease management.

Skin Biology and Diseases: Biology and Heritable Diseases of Skin

Understanding the basic biology of skin, such as the study of its underlying structures and processes and their interactions, is essential for developing treatments for skin diseases. In turn, the identification of causative genes in single gene diseases affecting human skin provides critical insights into basic skin biology. Because all cells in the body are genetically identical, many of the differences between cell types are caused by epigenetic effects, which can also be inherited. Advances in epigenetics and epigenomics research may enable novel studies of the effects of nutrition, environmental factors, and aging on skin.

The application of powerful new technologies, such as high-throughput assays, bioinformatics approaches, and complex animal models, are revolutionizing the field of skin research. These tools have supported a shift in focus from the effects of individual proteins to the study of entire regulatory pathways. Overarching themes that incorporate new technologies and perspectives are governing many studies in skin biology and diseases.

Broad areas of potential research directions include:

  • Apply high-throughput genomic and epigenomic technologies, combined with mathematical and bioinformatics methodologies, to elucidate the regulatory networks involved in normal skin biology and disease states.
  • Investigate the function of noncoding RNAs, including microRNAs, in skin stem cells and in development and differentiation.
1. Molecular and cellular biology

Skin has unique molecular and cellular properties because of its protective functions and its stratified (layered) structure. The outer layer of the skin, the epidermis, is composed mainly of keratinocytes, which are the main contributors to skin's barrier function. The epidermis undergoes rapid and continuous, life-long renewal, a process driven by a rich population of stem cells (see box below). A number of skin appendages (e.g., hair follicles and sebaceous glands) are derived from the epidermis and are essential for normal skin function. Melanocytes are also important components of the epidermis and are responsible for producing the pigmentation that protects skin from ultraviolet radiation. The stratified structure of skin creates complex cellular interactions and microenvironments, most notably the epidermal-dermal junction at the basement membrane. Compared with the epidermis, the dermis has a lower density of cells and is mainly populated by fibroblasts. The intercellular space of the dermis contains fibrous proteins, such as collagen, which is the main component of the extracellular matrix. The extracellular matrix is of particular importance to skin's function as an immune organ (e.g., as a medium of cell trafficking), as a sensory organ (e.g., as the home of a number of biosensors), and in wound healing (e.g., as a coordinator of the repair process).

Stem cells in skin: Stem cells have the ability to renew themselves and to generate progeny that differentiate into more specialized cells that maintain the integrity of the epidermis and skin appendages. Although homeostasis of the epidermis depends on epidermal stem cells, this area is poorly understood. Studies have revealed that hair follicle stem cells contribute to wound healing1. Pluripotent stem cells, which can differentiate to a number of cell types, reside in skin. These include skin-derived progenitor (SKP) cells from the dermis. SKPs help neurons develop and are being tested in animal models for potential use in nerve regeneration.

Induced pluripotent stem (iPS) cells are seen as alternative pluripotent stem cells to embryonic stem cells, for developmental biology research, as well as a potential cell source for regenerative medicine. Some of the pioneering work and most significant advances in generating iPS cells have been accomplished with easily accessible skin cells2 (dermal fibroblasts, cells from plucked hair follicles, keratinocytes). iPS cell research may create opportunities for gene correction in diseases with single-gene defects, as well as improved artificial skin for grafting. iPS cells may have advantages over embryonic stem cells for regenerative medicine, because they may circumvent problems with allograft rejection as well as ethical concerns.


1 Ito M, et al., Nat Med 2005. PMID: 16288281
2 Takahashi K et al., Cell 2007. PMID: 18035408


Broad areas of potential research directions include:

A. Epidermis and epidermal appendages
  1. Stem cells
    • Identify and characterize epidermal stem cells, including regulatory mechanisms that control self-renewal and lineage commitment, and the role of these cells in epidermal development, homeostasis, wound healing, and skin cancer.
    • Examine other pluripotent and multipotent stem cells in skin, such as SKP cells and neural crest-derived stem cells, to determine their origin and role in skin homeostasis, and as potential sources of stem cells for regenerative medicine.
    • Define the unique components and properties of the stem cell niche, and how this niche maintains the stem cell population.
  2. Keratinocyte growth and differentiation
    • Delineate the molecular signals in the differentiation pathways of skin cells and hair follicle cells, in vitro and in vivo, to understand defects in disease conditions, to identify potential therapeutic targets, and to guide the transformation of iPS cells into differentiated keratinocytes.
    • Investigate the structure and function of the protein complexes that maintain the structural integrity of the epidermis—such as desmosomes, hemidesmosomes, and the cytoskeleton—and the related genetic defects that contribute to the pathogenesis of pachyonychia congenita, forms of epidermolysis bullosa, and other diseases.
  3. Hair follicles and sebaceous glands
    • Elucidate the mechanisms that lead to the formation of new hair follicles in adults, towards the development of therapies for alopecia and for regenerative medicine.
    • Research the biology of the sebaceous gland, to inform the development of acne therapies.
  4. Melanocyte biology and pigmentation pathways
    • Study the interactions of melanocytes with other cell types, for insights into pigmentation pathways, skin homeostasis, and skin diseases.
    • Explore the molecular and genetic differences between pre-neoplastic nevi and senescent nevi that do not develop into invasive melanomas.
    • Identify the genetic and molecular basis of inherited pigmentation disorders, such as oculocutaneous albinism, and how genetic differences in pigmentation pathway genes influence skin cancer susceptibility.
B. Dermis
  1. Cellular components
    • Investigate the biology of normal fibroblasts and the alterations that lead to the deposition of abnormal extracellular matrix, to understand the role of fibroblasts in diseases such as sclerosis and fibrosis.
    • Elucidate interactions between epidermal and dermal components that are crucial for normal processes such as hair follicle development and hair cycling, and define the role for these interactions in diseases such as skin cancers.
    • Define dermal fibroblast diversity in different body sites, to understand the cell types involved in skin diseases that preferentially affect distinct parts of the body.
  2. Extracellular matrix
    • Study the mechanisms that regulate the normal assembly, interactions, and function of the molecular components of the extracellular mat (e.g., collagens, fibrillins, matrix metalloproteinases).
    • Investigate diseases (e.g. fibrosis, scleroderma), including heritable diseases (e.g. Marfan syndrome, Ehlers-Danlos Syndrome, dystrophic and junctional epidermolysis bullosa) caused by abnormal function and mutations in extracellular matrix components and regulatory pathways.
    • Explore the role of extracellular matrix remodeling in normal wound healing and diseases (e.g., chronic wounds, keloids), and the effects of ectopic mineralization (e.g., pseudoxanthoma elasticum).
  3. Vasculature
    • Expand our understanding of the mechanisms controlling angiogenesis and blood vessel structure and function in normal skin development.
    • Investigate the molecular and genetic defects in skin vascular components that cause cutaneous vascular malformation or affect angiogenesis in chronic wounds, psoriasis, and skin cancer.
C. Neuroendocrine and sensory functions of skin
  • Study the skin as a sensory organ and biosensor, and investigate the mechanisms of itch and pain, to inform the development of therapies to control these debilitating symptoms common to many skin diseases.
  • Elucidate the neuroendocrine function of skin, the stimulation of specific hormones by ultraviolet radiation exposure, and the effects of stress and the nervous system on skin components and skin disease severity.
  • Investigate central nervous system-endocrine-immune interactions that contribute to disease mechanisms and clinical symptoms.
2. Developmental biology

Signaling pathways or individual genes identified in skin development research provide important insights into what causes skin disease. Knowledge of developmental biology principles is also essential for successful regenerative medicine approaches (see Regenerative Medicine below). Increased understanding of hair follicle stem cells and the formation of new hair follicles (neogenesis) has revealed that adult skin has more regenerative capacity than previously thought. Animal models have been critical for determining the role of individual genes and regulatory pathways in these processes.

Broad areas of potential research directions include:

  • Develop animal models to study specific genes and regulatory pathways in the development of skin and its appendages, including the use of cell type-specific knockouts and overexpression.
  • Apply high-throughput, genome-wide technologies to explore the role of noncoding RNAs, including microRNAs, and epigenetic modifications on skin development.
  • Elucidate interactions between components of the dermis and epidermis that generate hair follicles, sweat glands, and sebaceous glands, such as the signals that activate the movement of hair follicle cells. Explore the potential to replicate these signals for therapeutic purposes.
  • Study the genetic basis of heritable diseases of skin development, known collectively as ectodermal dysplasias, to provide insights into the regulatory pathways that are critical for the development of skin and its appendages.
3. Skin barrier structure and function

A major function of the skin is to prevent water loss from inside the body and to prevent the penetration of chemicals and other environmental insults from outside the body. Breakdown of the skin's barrier function has emerged as a potential contributor to several diseases. For example, recent discoveries have shown that defects in the filaggrin gene (that encodes a protein involved in the skin barrier) contribute to the pathogenesis of several diseases, including atopic dermatitis and ichthyosis vulgaris, as well as the interaction of immune and barrier functions in skin.

Broad areas of potential research directions include:

  • Explore the structure and function of the skin permeability barrier (the stratum corneum), and how it changes with skin aging and in diseases (e.g., atopic dermatitis). Identify targets for therapies to restore normal barrier function in disease.
  • Identify the genes that contribute to defects in the skin barrier, especially in common skin diseases such as atopic dermatitis.
  • Determine how changes in the skin barrier in injured or diseased skin affect drug concentrations in the skin during topical therapy.
  • Study epidermal function as a barrier to transported molecules to inform the development of delivery methods for topical agents.

Skin Biology and Diseases: Immunobiology and Immune Mediated Diseases of Skin

The immune system's outpost in the skin is a critical protective mechanism against pathogens attempting to gain entry into the body. Dysfunction of immune system components has also been associated with skin diseases, such as psoriasis and autoimmune blistering disease.

1. Skin as an immune organ

The skin houses a variety of immune cells, such as T cells, Langerhans cells (antigen-presenting cells that are unique to skin), macrophages, and mast cells. Dendritic cells, such as Langerhans cells, are essential components in immune surveillance. Many immune cell types play important roles at different stages of wound healing, and mast cells and neutrophils provide a first-line response to pathogens. Research findings on the role of anti-microbial peptides (AMPs) in skin homeostasis and disease have opened new avenues to understanding psoriasis and atopic dermatitis, which are accompanied by increases and decreases, respectively, in AMPs.

Broad areas of potential research directions include:

  • Study the skin as an active immune organ, focusing particularly on immunocompetent cells that both reside in and traffic through skin, since these cells are important for immune surveillance of microbes and cancer, and for diseases like psoriasis, vitiligo, alopecia areata, atopic dermatitis, and contact dermatitis.
  • Analyze the impact of increases and decreases of skin AMPs (e.g., cathelicidins, β-defensins), and changes in the skin microbiome, in concert with disease conditions or vaccinations (e.g., smallpox).
  • Investigate imaging and nanotechnology approaches for studying skin structure and in situ trafficking and interactions of immune cells in skin.
  • Define the role of the immune system in the initiation, development, surveillance, and treatment of skin cancer.
2. Inflammatory and immune skin diseases

Skin is the primary or exclusive target organ of many autoimmune diseases. Several immune mechanisms of autoimmune skin diseases have been uncovered, including the role of T cell subsets and cytokine pathways in psoriasis.

Genome-wide association studies and linkage association studies have yielded important results for complex skin disorders, such as psoriasis and vitiligo, and have revealed genetic associations with other autoimmune diseases and co-morbidities through the identification of shared or converging molecular and cellular pathways. For example, SNPs have been found in both psoriasis and Crohn's disease, and genetic loci for increased risk for rheumatic diseases and other autoimmune diseases have been identified among family members of vitiligo patients. These genetic and biochemical studies reveal important insights into aberrant disease mechanisms and may lead to the development of treatments (see box below).

Breakthroughs in psoriasis genetics and therapies: Recognition of the frequency of psoriasis within families launched the search for susceptibility genes for this disease, and research has borne fruitful insights in recent years. Many of the discoveries can be attributed to well-organized collaborations between research groups across the United States and the globe, which combined the efforts of dermatologists, immunologists, geneticists, and biostatisticians. These studies revealed genetic mutations that altered functional pathways of the immune system1, and some of these modified mechanisms have also been associated with other autoimmune diseases. The studies led to the development of biologic treatments that target the defective pathways associated with autoimmune diseases. One of these biologic treatments has been shown to be an effective treatment for psoriasis2—a prime example of the value of genetics research for generating safe and efficacious therapy. Additional studies are being conducted in specific ethnic groups to identify psoriasis susceptibility genes that might be associated with certain populations, to further the development of gene-directed therapies and personalized medicine.


1 Nair RP, et al., Am J Hum Genet. 2006. PMID: 16642438
2 Krueger GG, et al., N Engl J Med. 2007. PMID: 17287478


New knowledge indicates that the innate immune system plays a role in skin inflammatory diseases via the inflammasome, a complex of proteins intrinsic to the innate immune system's function that drives a cascade of inflammatory cytokine activation (see Innate immunity under Immune and inflammatory Mechanisms in the Arthritis and Rheumatic Diseases section, for more information on inflammasomes). The role of the inflammasome and interaction of the innate and adaptive immune systems in skin diseases, such as psoriasis and psoriatic arthritis, are promising avenues for future research.

Broad areas of potential research directions include:

A. Genetic studies
  • Use linkage and family studies to pursue skin disease-associated loci identified by genome-wide association studies, to understand disease risk and pathogenic pathways, and to identify multiple genetic variants that may contribute to complex diseases.
  • Integrate functional and mechanistic studies, proteomics, and metabolomics with genes and loci found by genetic and genomic approaches, to investigate the relationship between genotype and phenotype, and to understand pathogenic mechanisms and disease progression.
  • Study the role of gene-environment interactions, the impact of epigenetics (heritable, non-coding DNA and histone modifications), and other modifiers of gene expression (microRNAs, small interfering RNAs) in pathogenesis.
B. Pathogenesis
  • Improve understanding of the process of autoimmunity, in general, and of autoimmune skin diseases in particular. These include pemphigus, pemphigoid, psoriasis, systemic lupus erythematosus, alopecia areata, vitiligo, vasculitides, and others (see the box T helper cell subsets under Adaptive immunity, Immune and inflammatory mechanisms in the Arthritis and Rheumatic Diseases section, for more information on autoimmune mechanisms).
  • Examine the mechanisms and control of inflammation in inflammatory skin diseases.
  • Delineate the physiological mechanism(s) underlying the common symptom of itching.
  • Clarify interactions between the innate and adaptive immune systems in inflammatory skin diseases, as well as the role of the innate immune system's inflammasome in diseases, such as psoriasis and psoriatic arthritis (see Innate immunity under Mechanisms of Disease, Immune and inflammatory mechanisms in the Arthritis and Rheumatic Diseases section, for more information on inflammasomes).
  • Investigate the impact of inflammatory and immune system cytokines on gene expression patterns that can contribute to perturbations in the skin, and the potential effect of shared pathways on co-morbidities, such as accelerated atherosclerosis.
  • Conduct research using normal-appearing skin from genetically susceptible people to study triggers of gene expression in diseases such as psoriasis, vitiligo, and alopecia areata. Investigate mechanisms involved in the development and progression of these diseases.
  • Study the role of the skin microbiome as a potential trigger for autoimmune and inflammatory diseases of skin.
  • Investigate the function of the most relevant skin disease-associated genes, using animal and in vitro models.
  • Characterize the most relevant, altered signal transduction pathways leading to inflammatory and autoimmune skin disease.
  • Explore the mechanisms by which autoantibodies cause blistering of the skin in the immunobullous diseases, to inform the development of drug therapies.

Skin Biology and Diseases: Wound Healing and Regenerative Medicine

The dynamic character of healthy skin and its components allows for tremendous regenerative capacity in response to injury. Tissue repair of skin, in situations of major trauma or impaired wound healing, brings together research in wound healing mechanisms and regenerative medicine.

1. Wound healing

The inability of chronic wounds to heal is a major health problem in the United States. This problem is expected to increase in magnitude as the nation's population ages and with the rising incidence of type 2 diabetes. Overcoming defects in chronic wound healing (e.g., lack of blood supply, altered behavior of epidermal stem cells, changes in systemic factors), preventing scar formation, and regenerating hair follicles and other adjoining structures are important goals in wound healing research. To battle these conditions, normal wound healing processes must be understood.

Broad areas of potential research directions include:

A. Mechanisms in normal wound healing
  • Study basic mechanisms of wound healing, such as the control of epidermal cell migration, maturation and differentiation, the derivation of dermal fibroblasts, and changes in the wound healing process that result in malignancy.
  • Develop systems biology approaches and animal models of human wound healing to study the complex interactions of multiple factors and pathways, such as keratinocyte migration, local wound blood flow, inflammation, and connective tissue turnover.
  • Use systems approaches to study wound healing, because morbidities may be caused by secondary physiological changes that are not directly associated with wound repair (see the next segment, Model Systems and Therapy Development, Model development, for more information on systems approaches).
  • Investigate the function of microRNAs in wound healing and regeneration.
B. Impaired wound healing
  • Research the milieu of slow-healing and chronic wounds to identify the factors that impair the healing process. These include microbial populations, hypoxia, inflammatory cytokines, and other physical and chemical properties.
  • Develop animal models of chronic wounds that more closely mimic human responses, to investigate new experimental therapies.
  • Define the molecular and genetic mechanisms in aberrant wound healing that lead to fibrosis or keloid formation.
2. Regenerative medicine

Treatment of acute skin wounds, such as extensive burns and the effects of war trauma, benefit from advances in regenerative medicine. Regenerative medicine in skin involves research on developmental processes, epigenetics, the skin microenvironment, and engineering approaches to create wound conditions conducive to rapid healing. The findings of this research provide new insights into the integration of exogenous components in tissue repair (see box above, Stem Cells in Skin), or in helping the body repair itself. Regenerative medicine efforts in skin include the development of artificial skin, which has evolved from simple keratinocyte sheets, into a multi-component, multi-layered material.

Broad areas of potential research directions include:

A. Stem and progenitor cells
  • Explore the therapeutic potential of various types of stem and progenitor cells, including skin stem cells, induced pluripotent stem (iPS) cells and embryonic stem cells, in the generation of artificial bioengineered skin replacements for acute and chronic wounds, and in the repair or regeneration of other tissues.
  • Examine iPS cells in long-term, in vivo transplantation studies, to better understand potential aberrations in cell behavior.
  • Develop methods for the in vivo tracking of exogenous cells in regenerative medicine applications, to determine if the cells play only a transient role, or whether they become incorporated into regenerated tissue.
B. Biomaterials and scaffolds
  • Apply knowledge gained from the study of skin biology and normal wound healing to design and engineer novel biological therapeutics and biomaterials that promote wound healing by directing the proper migration, growth, and differentiation of skin cells.
  • Explore the use of natural extracellular matrix components as biomaterials that provide appropriate structural and mechanical properties for generating functional skin. Develop biomaterials and scaffolds that mimic or result in functionally superior extracellular matrix.
  • Elucidate the impact of mechanical load on blood flow and connective tissue turnover with or without biomaterials and scaffolds.
  • Develop wound coverings from bioengineered skin that has been genetically manipulated to produce growth factors in a sequence that replicates normal skin regeneration.
C. Molecular and genetic-based therapies
  • Investigate effective in vivo molecular and genetic delivery strategies with optimal functional outcomes and minimum adverse responses for the enhanced healing of acute and chronic wounds.
  • Develop ex vivo gene correction strategies for the treatment of single gene skin diseases.

Skin Biology and Diseases: Model Systems and Therapy Development

1. Model development

To advance biomedical research and therapeutic development, information from in vitro and genomic research must be evaluated in the complex context of living organisms. Animal models are essential for preclinical, in vivo experimentation. Genetically manipulatable mice and many existing, well-characterized, inbred mouse strains are powerful tools for much current research. However, finding suitable models for skin research has been challenging. The transplantation of human skin to a mouse, or reconstituting the human immune system in a mouse, may be useful for investigating some skin diseases. Complex diseases are unlikely to be recapitulated with transgenic animal models, but zebrafish, fly, and other new systems have potential for modeling skin diseases and mutations, as well as for high-volume screening. Some polygenic diseases have emerged spontaneously in mice (e.g., alopecia areata) and can be maintained with proper breeding procedures.

Cultured skin substitutes and other in vitro models of skin are in current use, particularly for toxicology screening. Grafts of human skin onto mice provide a system to examine molecular and cellular processes, such as the development and progression of squamous cell carcinoma over time and in a controlled, experimental environment.

Systems biology is a research approach used to understand the network behavior of biological systems, in order to predict the behavior of perturbations in the system or to develop novel ways to modulate the system's behavior. In these approaches, detailed, quantitative data from multiple sources are combined with conceptual and mathematical modeling of a system's components and their interactions. To support the development of rigorous model systems, it will be critical to attain consensus on standards for collecting and reporting research results such as gene expression, epigenetic, and genome-wide association data, will be critical.

Broad areas of potential research directions include:

A. Animal models
  • Develop animal models to study the role of specific genes and regulatory pathways on the development of skin and its appendages, as well as on skin homeostasis.
  • Create animal models to study the trafficking of cells (e.g., immune cells) in live skin, and to visualize stem cell populations and their progeny.
  • Generate and validate animal models that mimic human skin diseases, including large-animal models, transplants of human skin, and reconstitution of the human immune system.
  • Explore the use of zebrafish, fly, and other genetically tractable model organisms for modeling skin diseases and mutations, and for high-throughput genetic screening.
  • Create small-animal models to facilitate high-volume screening of therapeutic agents.
  • Generate animal models to investigate the mechanisms of tissue damage by toxic industrial chemicals and chemical threat agents, and for testing the efficacy of potential countermeasures.
B. In vitro cell-based models
  • Develop 3D models of normal human skin and of skin diseases, such as skin carcinogenesis and inflammatory diseases, to conduct high-throughput screening of chemoprevention and therapeutic agents.
  • Create 3D skin equivalents for toxicology studies and for testing transdermal and transepithelial delivery systems, in high-throughput platforms.
  • Use patient-derived iPS cells to create disease models to study pathogenesis, as well as to test therapeutic agents for personalized medicine approaches.
C. In silico modeling
  • Examine the regulatory network of genes, proteins, and cells (using data from high-throughput devices, genomics, proteomics, metabolomics, and bioinformatics).
  • Encourage collaboration between biologists and mathematicians to enable the use of systems biology approaches to model complex biological systems.
  • Facilitate interactions between clinicians, mathematicians, and biostatisticians, for the development of models of disease and treatment outcomes and cost-effectiveness, to inform clinical trial design and clinical practice.
2. Biological and small molecule therapeutics

Knowledge of pathogenic pathways, as well as basic skin biology, allows the development of small molecule and biologic therapies (e.g., monoclonal antibodies) that target specific components of these pathways. These approaches facilitate effective and systemic treatment with minimal side effects, which is often required for widespread lesions from skin diseases.

Broad areas of potential research directions include:

  • Translate gene-based discoveries into novel therapeutics.
  • Utilize high-throughput, in vitro assays to screen large chemical and biochemical libraries, including FDA-approved drugs, for potential therapeutics.
  • Study small molecular activators and inhibitors of cellular processes as potential therapeutic agents.
  • Develop novel biological therapies for skin diseases using knowledge gained from studies of the biology and immunology of normal and diseased skin, genetic analyses, and the results of high-throughput genomic and proteomic studies of normal and diseased skin.
  • Investigate the mechanisms of action of therapeutics that are effective in non-skin autoimmune conditions, and determine whether they may be applicable to autoimmune skin diseases.
  • Develop interventions that reverse, not merely delay, the adverse changes that occur in aging skin.
3. Gene therapy

For inherited skin diseases caused by mutations in single genes, such as epidermolysis bullosa simplex, there is the possibility of replacing or correcting the defective gene, thus addressing the root cause of the disorder.

Broad areas of potential research directions include:

  • Develop in vivo and ex vivo gene therapy approaches, targeting well-characterized, single gene causal defects in skin diseases (e.g., various forms of epidermolysis bullosa).
  • Investigate the use of small interfering RNAs to treat skin diseases through the modulation of expression of both normal and defective genes.
A. Cutaneous and transcutaneous drug delivery
  • Apply findings from basic research in skin structure and function to inform the development of dermal drug delivery systems.
  • Investigate novel methods to treat skin diseases using topical delivery of small molecules as well as larger biomolecules, such as enzymes, monoclonal antibodies, and nucleic acids.
  • Develop transcutaneous drug delivery strategies for efficient and controlled administration of biological therapeutic agents for systemic diseases.

Skin Biology and Diseases: Clinical Research

Skin diseases, which frequently create enormous quality-of-life issues, are not always seen as important research targets relative to illnesses with greater mortality and morbidity such as cancer and cardiovascular disease. However, the impact of these diseases on patients' lives is significant, and some skin diseases are accompanied by systemic effects and co-morbidities.

1. Clinical trials and outcomes measures

Rapid translation of research findings to the clinic is unique to skin research, because topical therapies can be tested with greater safety and control than systemic treatments. Combination therapies, evidence-based comparison of treatments, and cost-effectiveness are critical topics for future research.

Broad areas of potential research directions include:

  • Develop clinical biomarkers that reliably predict disease progression and treatment outcomes and can be used as surrogate endpoints in clinical trials.
  • Create the resources required to move promising biomarkers from the bench to the clinic using state-of-the-art statistical, analytical, and computational methods.
  • Research novel, non-invasive imaging technologies and biomarkers for screening and early diagnosis to assess therapeutic outcomes and to identify the margins of malignant skin cancers.
  • Investigate new outcomes instruments that better measure disease severity and provide uniform descriptions and data that are comparable across studies.
  • Explore alternative designs of clinical trials for rare skin diseases in which cohort sizes may be very small.
2. Epidemiology and health services research

The incidence and morbidity of skin diseases are important subjects for epidemiological research. The distribution of health services for skin diseases is an example of the treatment of illnesses with low mortality but significant physical and quality-of-life effects.

Broad areas of potential research directions include:

  • Combine analysis of the natural history of disease with population-based epidemiological studies to determine disease prevalence.
  • Facilitate observational and epidemiological studies of skin disease co-morbidities and gene-environment interactions that may trigger or exacerbate skin diseases.
  • Apply genome-wide association study discoveries in related diseases and co-morbidities of skin diseases to understand shared pathways.
  • Investigate whether therapeutic invention for a skin disease modifies the risk for developing co-morbidities.
  • Study the pharmacogenomics of responders and non-responders to pharmacologic and biological interventions in skin diseases, in order to direct therapies to appropriate subsets of patients.
  • Examine the cost-effectiveness and comparative effectiveness of therapies, and combination therapy approaches for skin disease treatment; develop the infrastructure needed to conduct these studies.
  • Research the effects of patient-health care system interactions in disease outcomes.
3. Prevention studies
  • Perform prevention studies that focus on risk factor reduction strategies and early intervention trials, to prevent onset or progression of disease.
  • Exploit the use of clinical detection of pre-neoplastic lesions as an opportunity to develop non-invasive imaging and telemedicine approaches.

Skin Biology and Diseases: Behavioral and Biopsychosocial Research

Environmental triggers of many skin diseases, such as ultraviolet radiation from the sun for skin cancer, are modifiable risk factors. These risk factors underscore the role of behavior as a contributor to disease and create the opportunity for prevention and intervention through behavior modification. Mortality is a rare outcome for the majority of skin diseases, but discomfort from wounds and itching can have tremendous impact on patients' quality of life and behavior. Patients with disfigurement from skin diseases are frequently affected by psychosocial problems due to social stigmas.

Broad areas of potential research directions include:

  • Explore measures, including behavioral modification and protective strategies, to prevent skin exposure to ultraviolet radiation, which has adverse effects during teenage years and cumulatively in aging populations.
  • Conduct behavioral and psychobiology studies that have the potential to improve understanding of the mechanisms of skin disease.
  • Study the mechanisms by which stress affects skin disease progression and wound healing, and how stress management techniques and interventions impact disease outcomes and response to therapy.
  • Determine how the placebo effect influences disease outcome and response to therapy.
  • Investigate the management of chronic symptoms, such as itching and pain, as well as ways to minimize the effect of these symptoms on sleep and overall quality of life.
  • Use biopsychosocial approaches to understand how gender and/or ethnic and/or socioeconomic differences influence clinical disease outcomes, symptom perception and management, and interactions of patients with the health-care system.
  • Incorporate use of patient-reported outcomes instruments into clinical trials in skin diseases, to assess the effects of therapy on disease-specific quality of life.

The Skin Biology and Diseases programs at the NIAMS cover basic, translational, and clinical research in skin, including work on the developmental and molecular biology of skin, the study of skin as an immune organ, and autoimmune, inflammatory, and genetic diseases of skin. These fundamental research findings contribute to the development of tools for clinical diagnosis, therapeutics, and disease management strategies.

III. Bone Biology and Diseases

The NIAMS bone biology and diseases programs cover a broad spectrum of basic, translational, and clinical research on the buildup and breakdown of bone. The acquisition and preservation of adequate bone mass, as well as the maintenance of the architectural and material qualities that confer strength on bones, are crucial for protection against fracture. Osteoporosis, or low bone mass, increases the risk of fracture with its attendant morbidity and reduced quality of life. Because osteoporosis is common among older people, particularly women past menopause, the prevention, diagnosis, and treatment of osteoporosis have major public health implications. Through its programs, the NIAMS supports studies of the regulation of bone remodeling; bone formation, bone resorption, and mineralization; as well as the effects of hormones, growth factors, and cytokines on bone cells. The Institute oversees several large epidemiologic cohorts that characterize the natural history of osteoporosis and identify genetic and environmental risk factors that contribute to fracture. These programs also support research on the causes, pathophysiology, and treatment of less common bone diseases, such as osteogenesis imperfecta and Paget's disease of bone, as well as on a wide range of developmental disorders of the skeleton, many of which are genetic in origin.

Bone Biology and Diseases: Biology and Physiology of Bone

1. Molecular and cellular mechanisms in bone

The key processes in bone remodeling are the formation of new bone by cells called osteoblasts, and the breakdown, or resorption, of old or damaged bone by cells called osteoclasts. In a healthy adult skeleton, these processes are balanced by the overall process of bone remodeling. Fully mature osteoblasts, called osteocytes, remain embedded in mineralized bone, and are emerging as a crucial population of cells for controlling bone physiology. An imbalance of resorption over formation results in bone loss, which can increase risk of fracture. Understanding the mechanisms that regulate the functions of osteoblasts, osteoclasts, and osteocytes, and hence influence bone resorption or bone formation, could yield new therapeutic targets. The ability to manipulate such mechanisms could also be essential for tissue engineering efforts using bone-forming cells.

Broad areas of potential research directions include:

A. Anabolic mechanisms: new bone formation by osteoblasts
  • Characterize the biochemical pathways that control the proliferation of osteoprogenitor cells.
  • Define the intermediate cell types in the differentiation of progenitors to mature bone-forming osteoblasts and identify the factors that regulate progression through the cellular lineage.
  • Elucidate the mechanisms that control osteoblast activity and determine a cell's functional lifetime.
B. Resorption of bone by osteoclasts, leading to bone loss
  • Characterize the biochemical pathways that control the differentiation of osteoclasts from progenitor cells in the monocyte/macrophage lineage.
  • Define the factors that regulate the maturation of progenitor cells into active multi-nucleated osteoclasts.
  • Elucidate the biochemical pathways that control osteoclast activity and functional lifetime.
C. Mineralization of the bone matrix
  • Define the mechanisms that initiate and control the deposition of calcium phosphate crystals in the collagen matrix of bone.
  • Elucidate the factors that control the extent of mineralization in bone, and determine the effect of varying degrees of mineralization on the mechanical properties of bone.
  • Explore the causes of pathological calcification of soft tissues and explore measures that could prevent or reverse inappropriate mineralization.
D. Cell-matrix interactions in bone
  • Characterize specific interactions between osteoblasts, osteoclasts, and components of the extracellular matrix of bone that influence cell differentiation or activity.
  • Determine interactions between osteocytes and the bone matrix to help explain processes underlying the embedding of the cells in mineralized matrix and the formation and maintenance of the osteocyte network.
  • Identify signaling pathways that are activated by cell-matrix interactions in bone.
E. Cross-talk between different bone cell types
  • Define the molecules that are produced in one cell type and influence another.
  • Elucidate sites where molecules that have effects on bone cells are produced.
  • Investigate the effects of signaling molecules originating in other cell types on target cells.
F. Mechanisms of fracture repair
  • Define the cell types and biochemical pathways involved in the recruitment of osteoprogenitor cells to fracture sites.
  • Elucidate the processes that lead to callus formation and remodeling of new bone, including the roles of inflammation and vascularization.
  • Identify and characterize the factors leading to fracture non-unions (i.e., fractures that fail to heal).
G. Response of bone to mechanical loading
  • Characterize the cell populations that mediate the anabolic response of bone to loading.
  • Define the role of the osteocyte network in mechanosensation and the response to loading.
  • Determine the resorptive response of bone to conditions of unloading, such as microgravity and disuse.
  • Elucidate the biochemical signals that are activated when bone cells are exposed to specific mechanical stimuli that may arise in bone under different loading conditions.
2. Integrated physiology and pathophysiology of bone

Over the past five years, the research community has made considerable progress in understanding connections between bone physiology and the broader network of biologic processes that involves many different organs and tissues. Scientists are now poised to make additional discoveries that will help to explain the connection between the skeleton and the central nervous system, the immune system, the kidney and gut, and energy metabolism (see box below). Bone can be either a target or a regulator, and it likely performs both roles as it interacts with various systems in development, aging, and disease. Bone and the events responsible for bone health are connected with other biologic processes; many drugs for conditions apparently unrelated to bone may have unanticipated effects on the skeleton.

New evidence that bone and fat metabolism are connected: The NIH's portfolio of basic bone biology research includes several projects that address the relationship between bone and fat. Bone and fat cells come from the same stem cells, and new findings suggest that mechanical stress may alter the proportion of stem cells that go on to form each tissue type1. Through other experiments examining the effects of diet on bone mass and body mass, NIH-funded scientists found a gene that influences how a person's skeleton responds to dietary fat2. That particular gene had long been known to be important for fat metabolism. Meanwhile, others who were studying molecules involved in bone building have made connections to the way the body burns fat3.

This work suggests that energy metabolism and bone metabolism may be linked. Energy metabolism underlies pressing public health issues such as obesity and diabetes. It may be valuable to consider osteoporosis (low bone mass, which leads to high fracture risk) as part of a regulatory network in which energy metabolism is an important influence. The identification of specific molecules and biochemical pathways that underlie obesity and osteoporosis could lead to new therapies. However, recent experience has also shown that drugs often have unexpected consequences, precisely because the drugs' targets often have roles in multiple tissues. Moreover, signals can arise in one tissue and act in another. Recognizing and understanding the complex web of interactions that exists between different tissues and metabolic pathways will be crucial to developing new therapies and using them effectively.


1 Rubin CT, et al. Proc Natl Acad Sci U S A. 2007. PMID: 17959771
2 Ackert-Bicknell CL, et al. J Bone Miner Res. 2008. PMID: 18707223
3 Rowe GC, et al. Endocrinology. 2009. PMID: 18772235


To fully appreciate interactions among organ systems, bone researchers will need to form interdisciplinary teams with scientists who specialize in other organ systems and metabolic pathways.

Broad areas of potential research directions include:

A. Bone physiology and energy metabolism
  • Characterize the factors that determine whether mesenchymal progenitor cells differentiate into osteoblasts or adipocytes.
  • Determine the influence of body mass and body composition on bone homeostasis and bone strength. Such research could include studies to explain the relationship between bone physiology and the regulation of distinct fat depots (e.g., subcutaneous, visceral, and marrow fat).
  • Elucidate the relationship between bone physiology and the regulation of glucose utilization.
B. Bone and the nervous system
  • Determine the influence of the central nervous system on bone physiology, including the effects of hypothalamic signaling and the influence of circadian rhythms.
  • Explore the roles of specific neurotransmitters and neuropeptides in bone.
  • Study the impact of psychiatric disorders and their treatment on skeletal health.
C. Bone and the hematopoietic and immune systems
  • Clarify the importance of interactions between bone cells and cells of the hematopoietic and immune systems, including factors in the bone marrow that influence bone physiology and bone remodeling.
  • Define the functions of regulatory molecules that may have roles in both bone physiology and the development and function of the immune system.
  • Examine the mechanisms underlying the destruction of bone in conditions of inflammation and autoimmunity.
D. Bone and the vascular system
  • Determine the relationship between angiogenesis (the formation of new blood vessels) and the processes of bone growth and remodeling.
  • Explore possible parallels between bone mineralization and the vascular calcification that occurs in cardiovascular disease.
E. Bone and cancer
  • Elucidate the mechanisms that underlie skeletal morbidity associated with malignancy, such as pathological bone destruction and formation.
  • Explore the nature of interactions between cancer cells and bone cells that mediate metastasis to bone.
F. Bone as a component of joints
  • Explore the interface between bone and cartilage in articular joints, including the possibility that signals originating in bone contribute to degenerative joint disease.
  • Identify and characterize the mechanisms that lead to pathological bone formation in joints, such as osteophytes (bone spurs) or spinal stenosis.
3. Genetics and genomics of bone mass and fracture risk

Heredity influences many aspects of skeletal physiology, including the changes that occur with aging. However, genetic influences on the skeleton are complex, reflecting the contributions of many different genes. Advances in technology for studying genetic variation and its impact on gene expression have enabled investigators to study genetic influences on health on a genome-wide level. This opens the door to unprecedented understanding of individual risk for disease, and for personalized approaches to treatment. To achieve these goals, the NIAMS is exploring ways in which it can facilitate application of genetic and genomic technology to long-standing problems in skeletal health. One approach is to make use of existing clinical cohorts that consist of thousands of people that have been well-characterized with respect to bone mineral density and other relevant clinical parameters, including the incidence of fractures (see box below). Adding high-density genotypic analysis and information about gene expression levels would enrich the value of rich phenotypic data sets. As such, the cohorts would be a valuable resource for studies to identify genetic risk factors for bone disease, as well as to discover new targets for therapeutic intervention.

Broad areas of potential research directions include:

A. Genome-wide association studies
  • Apply genome-wide association methods to identify genetic variants associated with differences in skeletal traits such as bone mass and quality, risk for osteoporosis and fracture, and response to therapeutic interventions.
  • Increase the number of available datasets that combine genome-wide genotype data with phenotypic data relevant to bone physiology and skeletal health.
  • Increase the representation of rare genetic variants in genome-wide association studies of skeletal phenotypes by utilizing family-based cohorts and exploiting genomic sequence resources.

Epidemiologic studies of osteoporosis: The NIH supports several prospective cohort studies, including the Study of Osteoporotic Fractures in women and Mr. OS, a study of osteoporosis and other age-related diseases in men. The studies, which have been ongoing since 1986 and 1999, respectively, identified specific characteristics associated with fracture risk in older Americans. Assessing risk is important because the devastating consequences of low bone mass are preventable. For example, simple changes to a person's home—adding more lights and removing clutter, for example—can prevent falls. A balanced diet and modest exercise build bone strength. And, medications can slow disease progression.

The NIAMS plans to build upon the findings of these and other large population study samples (e.g., the Framingham Osteoporosis Study, the Women's Health Initiative) by encouraging researchers to apply the data to genome-wide association studies of bone mass and fracture risk and by expanding access for additional studies through the NIH-wide genotype-phenotype database dbGaP.

For further information, see:

NCBI dbGaP (


B. Linking the genome to gene expression
  • Apply high-throughput methods of transcriptome and proteome analysis in humans and animal models. Such studies can assess the impact of genetic variation and skeletal health status on gene expression patterns.
  • Explore events at the epigenomic level—including histone modification, chromatin organization, and the role of non-coding RNAs—that may be relevant to skeletal health.

Bone Biology and Diseases: Developmental Biology and Stem Cells

1. Skeletal development

The shaping and growth of bones during infancy and childhood are important for adult skeletal health. Research into the processes by which bones originate in the embryo and grow during maturation of the skeleton promises to illuminate causes and treatments of developmental disorders in humans. This knowledge may also lead to more effective methods for enhancing repair and regeneration of bone damaged by disease or trauma.

Broad areas of potential research directions include:

A. Early skeletal formation and growth
  • Elucidate the mechanisms that establish the location and shape of bones as they form during embryonic development.
  • Identify and explore mechanisms that control the cartilage-to-bone transition during endochondral ossification, including chondrocyte hypertrophy and apoptosis, mineralization, and the role of vascular ingrowth.
B. Disorders of skeletal development
  • Define the causal factors underlying disorders of skeletal development, such as the osteochondrodysplasias. Such research would include the roles of specific genetic mutations.
  • Investigate the biological mechanisms that underlie the effects of mutations linked to disorders of skeletal development as well as the cellular and molecular consequences of these genetic changes on developmental processes.
2. Stem cells

Bone cells differentiate from less specialized progenitor or stem cells, which can produce several different types of cells in response to various biochemical signals. Understanding these cells and the signals that guide them could improve tissue engineering and regenerative medicine approaches. Stem cells are also important targets of gene-based therapy strategies for genetic diseases of bone.

Broad areas of potential research directions include:

A. Mesenchymal progenitor cells
  • Define mesenchymal cell lineages to identify multi-potential precursors (adult stem cells) with osteogenic potential; explore whether the tissue from which these cells originate (e.g., marrow or adipose) influences their differentiation potential.
  • Investigate the effects of regulatory factors, such as growth factors and bone morphogenetic proteins, on the differentiation of progenitor cells.
B. Embryonic and pluripotent stem cells
  • Examine the properties of animal and human embryonic stem cells with respect to osteogenic differentiation. Such research might include responses to specific growth factors and other regulatory molecules.
  • Explore the potential of iPS cells for differentiation along the osteogenic pathway. Studies could include investigating the differences between induced and embryonically derived stem cells and the effects of different strategies for inducing pluripotency.

Bone Biology and Diseases: Imaging and Biomarkers of Bone Quality and Fracture Risk

Simple assessments of bone mass or mineral content fail to take into account the large contributions of bone geometry, microarchitecture, and material properties that affect the ultimate mechanical performance of bone. Dual energy x-ray absorptiometry (DXA), the standard clinical measurement of bone density, is widely available and economical, but it gives only a rough estimate of bone quality and fracture risk. Understanding how architectural and material factors contribute to bone strength, and developing better methods of assessing these factors in the clinic, could lead to improved fracture risk prediction and monitoring of response to treatment.

Broad areas of potential research directions include:

1. Non-invasive measures of bone quality and fracture risk
  • Analyze the architectural and material factors that influence mechanical performance of bone by direct study of specimens and by modeling and engineering analyses.
  • Develop and validate non-invasive measures of bone quality (such as those based on magnetic resonance, computed tomography, and ultrasound) that could improve the clinical assessment of fracture risk. Such measures would also provide early indications of the effectiveness of therapies.
2. Outcome measures and surrogate markers
  • Identify biochemical markers of bone strength and fracture risk that can be measured in easily obtainable biomaterials such as serum or urine.
  • Test candidate biomarkers in well-characterized clinical cohorts for which bone mass, bone quality, and fracture risk can be assessed independently.

Bone Biology and Diseases: Preclinical and Translational Research

Interactions between laboratory and clinical researchers are essential for translating basic discoveries into new drugs, treatments, and diagnostics. They also foster environments in which clinical observations can prompt cellular and molecular studies that characterize a disease mechanism.

Broad areas of potential research directions include:

1. Pathobiological mechanisms
  • Characterize the molecular and cellular mechanisms underlying bone loss in common conditions such as sex hormone deficiency, vitamin D insufficiency, chronic inflammation, and steroid drug treatment.
  • Define the biological mechanisms underlying pathology in rare bone diseases, such as osteogenesis imperfecta and Paget’s disease of bone; apply knowledge of potential therapeutic targets to develop and test new interventions against rare bone diseases.
  • Examine biological processes that contribute to bone loss around orthopaedic implants and develop bone-preserving strategies for implant recipients.
  • Develop pre-clinical animal models that represent more accurately the initiation and progression of bone disease in humans.
2. Therapeutic mechanisms
  • Define the biological mechanisms underlying the effects of widely used medications, including drugs prescribed to prevent or reverse bone loss.
  • Determine the effects of drugs prescribed for diseases of other tissues and systems, since these drugs may have an impact on bone quality or fracture risk.
3. Gene-based therapies
  • Develop methods for the recovery and re-introduction of cells in the marrow stromal/osteoblast lineage; explore the potential of embryonic and iPS cells as mediators of gene-based therapies.
  • Discover innovative ways to effect genetic modification of cells for the correction of genetic defects or the manipulation of gene expression for therapeutic purposes.
  • Establish methods for the inactivation of genes using strategies such as viral vectors and small interfering RNAs.

Bone Biology and Diseases: Clinical Research

1. Personalized medicine and clinical trials

Characterization of disease mechanisms in the context of clinical studies may enable researchers and health-care providers to distinguish between disease subtypes that produce similar endpoints (e.g., fracture). Furthermore, improved understanding of individual genetic variation is expected to lead to improved prediction of who will respond best to different types of therapy. The NIAMS portfolio includes several studies that researchers could mine for information about variations in disease manifestations and patients’ responses to treatment.

In addition to examples identified under Imaging and Biomarkers, above, broad areas of potential research directions include:

A. Clinical trials
  • Assess the potential of combining therapeutic agents to achieve additive or synergistic treatment benefits.
  • Improve adherence to clinical protocols by developing and testing less burdensome dosing regimens or routes of administration and exploring approaches that reduce drug side effects.
  • Compare the effectiveness of different therapeutic approaches.
  • Develop and validate novel outcome measures and surrogate markers that can be used to improve clinical trial efficiency.
B. Personalized medicine
  • Develop improved predictors of fracture risk that likely will reflect aspects of an individual’s environment, lifestyle, and medical history.
  • Explore the co-morbidity of bone diseases with other health problems and examine possible interactions between bone-active drugs and medications prescribed for other conditions.
  • Investigate the effect of genetic variation on response to treatments.
2. Disease prevention and health promotion

The NIAMS recognizes the importance of maintaining wellness in healthy populations and enhancing the well-being of those who experience bone disorders or diseases. Because motivating behavior change at a population level is an issue facing many NIH components, it may be possible to integrate research on bone health messages with other health programs that include diet and exercise components. Social science approaches should be incorporated, where appropriate, into proposed research strategies.

Broad areas of potential research directions include:

A. Nutrition
  • Define the impact of nutritional status (e.g., vitamin D levels, protein intake) on bone health and fracture risk.
  • Develop and test strategies to promote bone health through improving the nutritional status of deficient populations.
B. Environmental and behavioral interventions
  • Develop and implement cost-effective strategies to promote healthy bone formation during infancy and childhood.
  • Examine the impact of physical activity levels on bone health and fracture risk; develop and test strategies to promote bone health through exercise and physical rehabilitation programs.

IV. Muscle Biology and Diseases

The NIAMS muscle biology and diseases programs encourage basic, translational, and clinical research on the biology and diseases of skeletal muscle. Studies address questions about muscle developmental biology, growth, and hypertrophy; mechanisms of muscle diseases and disorders; the physiology of muscle contraction; and the structural biology of the contractile apparatus. These programs support the development and testing of interventions against muscle diseases and disorders. They include cell and gene therapies, and small molecule and biological drugs. The programs foster research to characterize muscle disease progression and to develop outcome measures. NIAMS funding of infrastructure, such as patient registries, facilitates research sponsored by the NIH and other public and private organizations.

The NIAMS participates in the Federal Muscular Dystrophy Coordinating Committee (MDCC) and encourages studies that address objectives delineated in the Action Plan for the Muscular Dystrophies. The plan—which the MDCC developed with input from experts in the fields of muscular dystrophy pathophysiology, diagnosis, treatment, and patient and family care—is available at . The NIAMS partnered with the National Institute of Neurological Disorders and Stroke (NINDS), the NICHD, and the NIH Office of Rare Diseases, to sponsor a workshop on Translational Research in Muscular Dystrophy. A summary of the meeting, which focused on research needs related to therapy development and testing, is available at

Muscle Biology and Diseases: Biology and Physiology of Muscle

1. Muscle development, growth, and maintenance

Understanding healthy and diseased muscle states requires basic research on skeletal muscle tissue development and maintenance. Studies of the pathways controlling muscle formation, for example, are likely to have implications both for diseases characterized by muscle deterioration and for the regeneration of muscle after injury.

Broad areas of potential research directions include:

A. Muscle development
  • Define the factors that influence embryonic cell fate and those that control cell proliferation, migration, and differentiation in myogenesis.
  • Elucidate the mechanisms underlying myogenic chemotaxis, adhesion, and fusion.
  • Identify and characterize elements that dictate tissue patterning (e.g., muscle size, shape, fiber composition) during development.
  • Investigate the development of fascia and other connective tissues of muscle (also see examples listed under Biology, Structure, and Function in the Musculoskeletal Biology and Diseases section).
  • Study the formation of the contractile apparatus, myotendinous junctions, and other complex structures comprising mature muscle.
B. Muscle growth and maintenance
  • Characterize the cell types (in addition to myoblasts) that contribute to muscle growth and maintenance. The NIAMS is interested in studies on the activation, migration, proliferation, and differentiation of various muscle stem cells, including satellite cells and other progenitors, during cell/tissue turnover and repair.
  • Define the factors that control muscle growth, fiber type determination, and hypertrophy. Of particular interest are studies of muscle gene expression and protein synthesis and their effects on muscle function, and maintenance and regeneration during circadian patterns or animal hibernation.
  • Elucidate the structure, assembly, and function of macromolecular complexes essential for skeletal muscle function and maintenance, including the dystrophin/glycoprotein complex, contractile apparatus, and ion channel complexes.
  • Examine the functional and gene expression differences among muscle fibers or myonuclei and uncover the differences (e.g., in gene expression patterns) responsible for muscle specialization.
  • Explore the molecular and biochemical changes that are responsible for differences in muscle mass, susceptibility to atrophy, and response to exercise that are seen in men and women or in people at different ages.
  • Investigate the tissue, cellular, and subcellular responses to environmental factors including exercise or disuse. Research into the regulation of muscle protein synthesis and accumulation by exercise and nutritional and other environmental factors is of interest.
  • Study the processes of autophagy and proteolysis as they relate to turnover of muscle fiber components.
  • Understand the effects of damaged myotendinous junctions on muscle function and explore factors promoting or inhibiting its endogenous repair.
2. Molecular mechanisms of muscle function and dysfunction

Studies of basic skeletal muscle cell biology and normal muscle physiology are likely to uncover new molecular pathways that researchers could use to develop treatments against muscle diseases. Likewise, an understanding of how specific molecular defects produce the abnormal phenotypes of muscle diseases will provide insights into normal muscle function. Studies of the mechanisms by which existing therapies work may lead to improved treatments with reduced side effects.

Broad areas of potential research directions include:

A. Atrophy, fatigue, pain, and weakness
  • Elucidate the mechanisms responsible for muscle pain due to physical activity, injury, or disease.
  • Identify and characterize shared signaling pathways associated with downstream pathologies (such as weakness and muscle wasting) that are common to many genetic and acquired diseases.
B. Disease mechanisms
  • Better understand dystrophies, channelopathies, inflammatory myopathies, and other muscle diseases. Through hypothesis-driven studies, identify disease mechanisms, with potential to uncover therapeutic targets.
  • Characterize the effects of gene mutations and epigenetic variations on muscle disease onset and progression.
  • Elucidate how defects in post-transcriptional and post-translational processing of gene products affect skeletal muscle.
  • Examine the factors responsible for selective targeting of muscles by disease processes.
  • Explore the mechanisms responsible for muscle pain, fatigue, or wasting associated with chronic or acute diseases of other organ systems (such as cancer cachexia).
  • Study disorders arising from environmental factors, including statin-induced myopathies; research the genetic and environmental factors contributing to these conditions.
C. Mitochondrial biogenesis, turnover, and function
  • Better understand the regulation of muscle mitochondrial function and turnover in normal and disease states.
  • Identify and characterize the factors responsible for the mitochondrial-dependent necrosis that is associated with various muscle diseases.
  • Understand the effects of exercise on mitochondrial biogenesis.

D. Structural, physiological, and biochemical mechanisms of muscle excitation/contraction coupling and force generation
  • Analyze the structure and assembly of macromolecular complexes—including the dystrophin/glycoprotein complex, contractile apparatus, and ion channels—that are essential for skeletal muscle function and maintenance.
  • Characterize the structures and define the functions of the contractile apparatus and of intracellular compartments such as the sarcoplasmic reticulum and T-tubules.
  • Define calcium’s role in contraction and explore strategies to restore muscle function by correcting intracellular, compartmental, and extracellular calcium concentrations.
  • Determine the mechanisms by which mechanical stimuli influence muscle assembly and turnover.
  • Investigate how muscle strain injuries affect the components and assembly of these macromolecular complexes.

E. Understanding and improving existing therapies
  • Explore the mechanisms of drugs that currently are used in the treatment of muscle diseases. For example, deciphering the mechanisms by which corticosteroids benefit patients who have some forms of muscular dystrophy may pave the way for the development of more efficacious drugs with fewer side effects.
  • Perform high-throughput screens of molecular libraries to identify compounds that can augment existing therapies for muscle diseases and disorders.
  • Study how exercise regimens and/or nutritional supplementation can impact the treatment of muscle diseases and disorders.
3. Integrated physiology and pathophysiology

Studying muscle as a system that interacts with other tissues and organs will provide insights into the weakness and fatigue that occur with numerous non-muscle diseases. This research will also explain how physical activity contributes to overall health and well-being, beyond simply improving muscle strength and cardiovascular fitness. Characterization of the mechanisms responsible for the connections between muscle and other organ systems will likely entail collaborations among researchers from multiple disciplines.

Broad areas of potential research directions include:

A. Immune and inflammatory responses
  • Characterize the positive and negative effects of inflammation on regeneration after exercise, injury, or disease. Identify how exercise causes inflammation and determine the role of inflammation in impairing or restoring muscle function.
  • Determine the mechanisms by which exercise alters immune responses in muscle and other tissues.
  • Identify genetic risk factors that may stem from differences in the immune and inflammatory responses among racial and ethnic groups. Already, such findings are beginning to elucidate immune response genes that may be important in myositis.
B. Fibrosis and scarring
  • Elucidate the cellular and molecular events that contribute to or prevent formation of fibrosis and scarring during disease progression and in response to injury.
  • Understand whether muscle fibrosis is a reversible event and understand the steps involved in this process.
C. Muscle as a metabolic tissue and endocrine organ
  • Define the metabolic and hormonal interactions among muscle, bone, and fat during normal, exercise, and disease states.
  • Examine muscle’s role as a heat-producing organ in the regulation of core temperature.
  • Explore the effects of temperature on muscle function.
  • Identify and characterize factors released into circulation during skeletal muscle activity that impact other tissue and organ systems.
D. Skeletal muscle atrophy and impairment from systemic diseases
  • Determine how muscle fatigue or pain is associated with chronic or acute diseases of other organ systems.
  • Explore the mechanisms that cause muscles and bones to atrophy during prolonged bed rest (often in the context of a critical illness such as cancer or heart disease).
  • Investigate skeletal muscle changes in cachexia (as it occurs with diverse conditions including AIDS, cancer, chronic obstructive pulmonary disease, congestive heart failure, and end-stage renal failure).
4. Genetics and genomics of muscle

Studies of the genetic determinants of muscle mass and strength, of efficient muscle repair and risk of atrophy, and of disease susceptibility and treatment response should provide a strong foundation for personalized medicine. Although many muscle diseases result from single gene defects, genome-wide association studies offer opportunities to clarify the genetic bases for differences in disease manifestations and treatment responses. The role of the environment in muscle function and that of genetics on susceptibility to environmental effects are also important for understanding the mechanisms responsible for variations in disease risk and manifestations.

In addition to examples under Integrated Physiology and Pathophysiology, above, broad areas of potential research directions include:

A. Gene-environment interactions
  • Define genetic variations that enhance or limit the normal anabolic responses of skeletal muscle to resistance or endurance training.
  • Identify and characterize genetic variations that affect susceptibility to atrophy or age-associated sarcopenia.
  • Study genetic variations that are contributing factors to the time of onset or the rate of progression of inherited muscle diseases.
B. Genetic studies of treatment responsiveness
  • Elucidate the genetic factors that contribute to or detract from the effectiveness of enzyme replacement therapy.
  • Examine genetic differences that influence responses to corticosteroid therapy.
C. Racial and ethnic differences affecting disease risk and manifestations
  • Determine the incidence and prevalence of muscle diseases in racial and ethnic groups.
  • Explore how the care of patients with muscle diseases is affected by socioeconomic factors.

Muscle Biology and Diseases: Imaging and Biomarkers

1. Advanced imaging approaches

Sophisticated imaging tools, including advanced magnetic resonance modalities, have the potential to assess skeletal muscle volume, lipid and water composition, and sarcolemma integrity as well as physiological and metabolic conditions within muscles (see box below). These parameters may predict subsequent changes in muscle function that could be valuable when assessing new drugs. Imaging data also may allow researchers to elucidate the pathogenesis of muscle diseases. Further development of imaging methods for intact animals or human patients is likely to continue to require interactions between muscle researchers and imaging specialists. The muscle research community should explore applying imaging advances from other fields (such as neurology) to its studies.

Broad areas of potential research directions include:

A. Magnetic resonance, ultrasound, light, and other imaging modalities
  • Compare imaging data with histology or histopathology data collected through biopsies from animal models of muscle diseases, or from patients.
  • Create information technology tools for analysis of muscle imaging data.
  • Develop non-invasive methods to quantify additional markers of muscle physiology and metabolism.
  • Improve imaging methods to assess fibrosis and adipose accumulation and to analyze muscle fiber length and orientation.

Skeletal muscle magnetic resonance outcome measures: Strategies for visualizing musculoskeletal soft tissues, including muscle, have advanced tremendously in the past decade. New or improved modalities now provide massive amounts of clinical information. Magnetic resonance approaches have the potential to non-invasively assess skeletal muscle volume, lipid and water composition, as well as structural integrity. These studies may reveal early surrogate measures that predict changes in muscle function, which could be valuable for designing efficient clinical trials.

The NIAMS convened a one-day meeting with a small group of muscular dystrophy researchers to discuss the value of magnetic resonance for monitoring progression and responses to treatment and for uncovering the pathogenesis of muscle diseases. Participants addressed factors that researchers should consider when designing studies to further develop magnetic resonance outcome measures for clinical trials.

For further information, see:

Meeting summary (


B. Validation of imaging biomarkers relative to functional measures
  • Validate imaging approaches as early surrogate markers for muscle function by conducting natural history studies of muscle diseases using imaging modalities, and applying/employing functional outcome measures.
  • Correlate imaging data with outcome measures of muscle function important to patients and their caregivers.
  • Design measures of muscle structure and composition that are more sensitive than functional outcomes for assessing disease-related changes over short periods of time.
2. Biomarkers and physiological outcome measures

Outcome measures used in trials of muscular dystrophies or other muscle diseases include serum biomarkers of muscle breakdown (e.g., serum creatine kinase), expression and localization of specific proteins analyzed in muscle biopsies, measures of muscle function (strength or resistance to fatigue), and measures of quality of life and psychosocial health. While each has merits and may be most appropriate for specific trials, other measures that are non-invasive and sensitive to early changes in muscle structure, composition, or physiology could accelerate clinical studies of muscle diseases.

Broad areas of potential research directions include:

A. Disease progression and stratification
  • Develop surrogate biomarkers and measures that can be quantified non-invasively and can predict changes in physical function, disease severity, the development of complications, or response to treatment.
B. Early detection
  • Use new biomarkers to facilitate disease diagnosis so that treatments to slow or halt disease progression can be started early when they are most helpful.

Muscle Biology and Diseases: Model Systems and Therapy Development

1. Model systems

The development of models of muscle function, dysfunction, and injury will facilitate studies of muscle development, maintenance, repair, and regeneration, as well as studies of disease pathophysiology. The models also will serve as a testing ground for therapeutic strategies. The NIH expects investigators to share animal models developed with NIH funds.

The NIAMS supports infrastructure to facilitate studies of small and large-animal models; for example, through the Wellstone Muscular Dystrophy Cooperative Research Centers program (

Broad areas of potential research directions include:

A. Animal model efficacy trials
  • Develop pre-clinical animal models for various muscle diseases, since there is a need for a greater diversity of animal models that more accurately reflect the clinical phenotypes and variations observed in patients.
  • Improve the accessibility of animal models to the research community.
  • Make full use of published standard operating procedures and existing facilities for testing interventions in animal models of muscle diseases. Continue to develop and publicize additional standard operating procedures where needed.
B. Functional measurements
  • Design and validate measures of animal activity and muscle function that correlate with human performance of daily living activities.
C. Human induced pluripotent stem (iPS) cells and other cells as disease model systems
  • Create human cell models of disease to study disease mechanisms and pathophysiology.
  • Develop human cell-based models for use in translational research strategies along with animal models, to assess interventions for testing in clinical trials.
  • Make cell-based high-throughput assays that can be used to screen libraries of therapeutic compounds. This strategy can be applied further to identify potential drugs for specific subgroups of patients or even for individual patients.
  • Study iPS cells from multiple patients to identify factors responsible for variations in responses to treatments.
2. Therapeutic strategies

Molecular, cellular, and biologic interventions offer the possibility of restoring function to a defective gene or compensating for the loss of gene function that characterizes many muscle diseases. These approaches, as noted in the box below, could advance treatments against diseases of muscle and other tissues. However, there are many strategies to explore and technical hurdles to overcome.

Muscle recovery after exercise or injury: In the past two years, NIH-funded scientists have published several reports on compounds that improve muscle function and endurance in animals. The hope is that this new knowledge can be applied to improve treatments for people who have certain muscle disorders, frailty, obesity, and other conditions in which exercise is known to be helpful but not always practical. For example, researchers have identified two drugs that, in mice, seem to confer many of the healthful benefits of long-term exercise by giving the animals more fat-burning muscle and better endurance1. This discovery extends earlier, more basic research that identified a protein that regulates several fat-burning genes in muscle cells. Other researchers, exploring the role of a protein found in immature muscle cells, discovered that creatine supplements taken by athletes play an important role in muscle repair2. Elsewhere, scientists have identified a disrupted molecular pathway that leads to fatigue after even mild physical exertion in mice with muscular dystrophy. Their study demonstrated that a signaling pathway that regulates blood vessel constriction in skeletal muscle after mild exercise is defective in mouse models for Duchenne muscular dystrophy and other myopathies3. This finding may lead to treatments for the post-activity exhaustion that affects many people with neuromuscular disorders.


1 Narkar VA, et al. Cell. 2008. PMID: 18674809
2 O'Connor RS, et al. J Physiol. 2008. PMID: 18420707
3 Kobayashi YM, et al. Nature. 2008. PMID: 18953332


The use of isolated cells for healing muscle tissue or gene delivery offers great therapeutic potential for muscle diseases and disorders. The application of these approaches faces many obstacles; survival and integration of grafted cells are low, and strategies to improve their dispersal are needed.

Understanding the natural repair processes after injury or while recovering from disease could also lay the foundation for improved therapies. Rebuilding muscle tissue and its vasculature requires expertise from researchers working in myogenesis, stem cells, tissue engineering, transplantation biology and muscle physiology.

Broad areas of potential research directions include:

A. Animal models for testing cell therapies
  • Characterize animal models of muscle diseases and injury for the study of cell therapies and regeneration.
  • Define the cell populations and extracellular and intracellular signaling mechanisms that promote tissue repair.
B. Characterization and regulation of surrogate genes
  • Identify genes that can compensate for a genetic defect (e.g., utrophin for mutated dystrophin) and develop strategies to control their activity.
C. Enzyme replacement therapy
  • Broaden the use of enzyme replacement therapies beyond glycogen storage diseases.
  • Develop strategies to prevent or manage immune response to long-term enzyme replacement therapy for those patients who have adverse reactions.
D. Gene therapy
  • Characterize the interactions among viral vectors, host cells, and the immune system.
  • Design strategies to minimize immune response to transgene products.
  • Determine factors that contribute to efficient gene delivery to skeletal muscle.
  • Develop viral vectors that do not trigger detrimental immune responses and are more effective at delivering genes to, and expressing genes in, skeletal muscle.
  • Improve upon existing routes of delivery, including isolated limb perfusion and systemic vascular injections.
  • Investigate strategies to re-administer therapies and promote long-term gene expression.
E. Inhibition of atrophy
  • Identify and characterize modulators of signaling pathways that increase muscle growth and satellite cell proliferation (e.g., myostatin inhibitors, IGF1 signaling agonists) to treat atrophy.
  • Study protease inhibitors and modulators of signaling pathways that regulate muscle protein degradation and autophagy.
F. Interference with pathogenic protein production or activity
  • Better characterize the structure, function, and regulation of small molecule chaperones that target misfolded proteins.
  • Design and test biologic agents that can promote muscle growth or modulate immune responses.
  • Develop strategies to alter RNA processing, prevent gene expression (e.g., RNA interference), or inhibit proteins that limit muscle growth (e.g., myostatin inhibition).
G. Modulation of muscle metabolism and activity
  • Develop therapeutics that enhance muscle strength and resistance to fatigue.
  • Identify and test therapeutics that enhance or substitute for the effects of exercise training on skeletal muscle.
  • Investigate compounds that improve muscle’s ability to metabolize energy sources.
H. Restoration of expression and function of proteins from mutated genes
  • Apply knowledge of endogenous gene-splicing mechanisms to strategies that can restore normal gene function.
  • Prevent transcription of the mutation-containing exons of genes that would otherwise interfere with the production of a functional protein. Antisense oligonucleotide-induced exon-skipping strategies are one promising approach.
I. Small-molecule drug therapies
  • Develop robust assays based on validated targets of muscle disease pathogenesis for screening molecular libraries.
  • Incorporate existing resources for high-throughput screening, chemical synthesis, and compound modification into studies of molecular therapies against muscle diseases.
  • Pursue pre-clinical studies in muscle disease models for drugs approved for other diseases.
  • Study the toxicity and efficacy of potential drug therapies in cell and animal models.
J. Therapeutic potential of mesenchymal, blood vessel associated, or muscle-derived stem cells, embryonic stem cells, and human iPS cells
  • Characterize the abilities of growth factors, extracellular matrix molecules, or overexpressed transcription factors to stimulate the engraftment, survival, proliferation, and differentiation.
  • Conduct hypothesis-driven comparisons of the migratory and regenerative potential of different cell types—especially research that could contribute to the design of expansion, purification, and delivery strategies for clinical studies.
  • Produce tracers and markers for tracking long-term outcomes of cell-based muscle therapies in animal models or in patients.
  • Study the immune response in muscle to transplanted cell types and factors in the environment of diseased or injured muscle that affect engraftment.

Muscle Biology and Diseases: Clinical Research

Numerous treatments of muscle diseases have demonstrated efficacy in animal models. However, obstacles remain in the translation of these strategies to clinical trials. Clinical trial design is limited by the availability of validated, effective outcome measures and data on disease progression. Data collected through natural history studies on genotyped patients should facilitate understanding of pathogenesis and aid in clinical trial design. Patient advocacy groups can play essential roles in engaging patients in research.

In addition to examples under Imaging and Biomarkers, above, broad areas of potential research directions include:

1. Clinical trials for safety and efficacy of treatments
  • Assemble and coordinate a clinical trials infrastructure that would improve protocols for the more efficient management of patients in clinical trials of rare muscle diseases.
  • Conduct clinical trials to study muscle diseases and disorders involving drugs, biological therapies, stem cells, gene therapy, or other approaches individually or in combinations.
  • Develop strategies to lessen the burden of study participation on patients and family members.
  • Standardize outcome measures to allow for comparisons of treatments addressed in different studies.
2. Genetic tests
  • Establish cost-effective methods of diagnosing muscle diseases. A precise molecular diagnosis (i.e., exact information on the nature of the mutation) is essential for many of the potential therapies that are moving into clinical trials.
  • Pursue pharmacogenomic testing strategies that will allow patients and their health-care providers to design optimal treatment regimens.
3. Natural history studies
  • Conduct longitudinal, observational studies to characterize the onset, progression and recovery from muscle diseases and disorders.
  • Define and validate outcome measures and determine the optimal time frame for conducting clinical trials based on patient age or disease status.
  • Generate clinical patient data to stimulate hypotheses of disease pathophysiology.
  • Use existing patient registries, repositories and clinical databases to study muscle diseases and disorders.
4. Nutrition and behavioral interventions
  • Determine how interventions such as nutrition, exercise, and physical therapy work. Such knowledge may lead to better treatments and improved compliance.
  • Develop and test specialized “prescriptions” of exercises to maintain function or restore health. Even if a therapy such as exercise or stretching has only modest effects on symptoms, it could make a meaningful difference in patients’ lives if combined with other interventions.

V. Musculoskeletal Biology and Diseases

The NIAMS musculoskeletal biology and diseases programs cover a broad spectrum of basic, translational, and clinical research centered on the interplay between the body’s muscles, bones, and connective tissues. These programs include research on developmental biology of connective tissues, tissue engineering and regenerative medicine for orthopaedic and other musculoskeletal conditions, joint structure and function, degenerative joint diseases, imaging methods, injuries and repair, implant science, and spinal disorders. Basic, translational, and clinical research interests related specifically to bone or muscle are addressed in their respective chapters within this plan.

Many conditions addressed by the musculoskeletal biology and diseases programs are those that become more prevalent and problematic with age. Americans over 65 are the fastest growing segment of the U.S. population. This shift in the country’s demographics emphasizes the need for prevention and treatment strategies for diseases and conditions that affect joints. Investments in basic biology, combined with burgeoning opportunities in fields such as genetics/genomics and stem cells, will result in improved clinical outcomes.

Musculoskeletal Biology and Diseases: Biology, Structure, and Function

1. Developmental biology

The development of musculoskeletal tissues is a complex, dynamic process involving the growth and differentiation of multiple cell types in a well-orchestrated manner. Multiple signal transduction pathways play important roles in coordinating this process and in regulating the expression of a large number of genes. Understanding the process by which a multicellular organism develops from its early, immature form into a fully mature form may deepen knowledge of disease mechanisms, regeneration strategies, therapeutic targets, and treatment design. For example, fundamental developmental biology relates to research efforts in tissue engineering and regenerative medicine.

Broad areas of potential research directions include:

A. Cell and molecular signals
  • Characterize the molecules and signaling pathways that regulate the cellular activities essential for development and maintenance of musculoskeletal tissues.
  • Define the molecules and signaling pathways involved in the cellular activities (e.g., stem cell renewal, pluripotency, and differentiation) that are essential for forming musculoskeletal tissues.
  • Elucidate the factors that control critical regulatory and signaling proteins specific to the development of tissues of the joint (e.g., articular cartilage, growth plate, ligament, and tendon), and the development of tissue interfacial regions.
  • Investigate the role of specific cell populations (e.g., tendon progenitor cells) in tissue development.
B. Connections to musculoskeletal disease research
  • Apply developmental biology knowledge to issues relevant to orthopaedic pathology, such as the formation of neoplasias, as well as the initiation and progression of the bone and cartilage defects that characterize osteoarthritis.
  • Link findings regarding the roles of mechanical and biochemical effectors on the development of healthy musculoskeletal tissues with therapeutic targets against orthopaedic or connective tissue conditions originating in childhood.
2. Molecular and cellular biology of cartilage and connective tissues

A complex series of biochemical pathways and cellular interactions underlie the physiology of cartilage and connective tissues. Much remains to be learned about the assembly and maturation of these tissues, as well as of the role of mechanical and biochemical effectors in these processes.

Broad areas of potential research directions include:

A. Articular cartilage and chondrocyte biology
  • Characterize the interactions between cartilage matrix proteins and determine how mutations in individual cartilage matrix proteins affect chondrocyte behaviors and overall tissue structure and function.
  • Elucidate factors that contribute to chondrocyte cell death under normal or pathologic conditions.
  • Identify the features of the articular chondrocyte that distinguish it from other forms of cartilage.
  • Investigate the structure and function of the bone-cartilage interface.
  • Study the role of mechanical stimuli on the formation, maintenance, and destruction of extracellular matrices.
B. Tendons, ligaments, and menisci
  • Assess the effects of mechanical loading on the structural organization of tendons and ligaments.
  • Define the role of tendon progenitor cells in development and repair.
  • Explore the structural organization and biogenesis of tendons, ligaments, and menisci, and their interfaces with muscle and bone. Mechanisms underlying enthesitis formation may be relevant to processes involved in joint degeneration.
  • Study mechanisms of tendinopathy to identify biomarkers and therapeutic targets.
C. Interactions among cell types and tissues
  • Characterize the regulatory regions of genes relevant to musculoskeletal tissues.
  • Examine the influences of various connective tissue components during normal joint maintenance and repair or during joint deterioration caused by disease.
  • Investigate whether biological activities leading to joint degeneration originate in the bone, interfacial tissues, ligaments, menisci, or synovia.
3. Pathogenesis of joint diseases

Degenerative joint diseases, including osteoarthritis, affect not only the articular cartilage lining bone surfaces, but also the joint components such as the subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles. Excessive, debilitating deterioration of joint tissues is a hallmark of these diseases, regardless of whether they are caused by an inherited mutation, developmental or post-traumatic joint instability, failure of the neuromuscular system to protect against repetitive loading, or metabolic events that cause excessive joint remodeling. Studies of the cellular and biomechanical factors responsible for disease progression or the promotion of healing likely will require multidisciplinary research teams.

Broad areas of potential research directions include:

A. Influence of biomechanics and injury
  • Determine the biomechanical (including gait) and biochemical factors that influence initiation of the joint changes associated with osteoarthritis, and the progression of these changes to severe, degenerative joint disease.
  • Evaluate biomechanical factors that influence joint deterioration after injury or during disease, or those that affect healing. Conduct research that may lead to potential therapeutic targets against damage to the ligaments, tendons, or menisci.
  • Identify post-injury joint changes that cause or predict degenerative joint disease.
  • Map variations in gene expression during healing, remodeling, and adaptation to injury and disease (particularly tendinopathy), with particular emphasis on the cellular and molecular signals that link mechanical loading to gene expression.
  • Track and model post-injury changes in animal models to better understand the course of joint repair or deterioration.
  • Understand the basic biomechanical effects and related biochemical changes from obesity that lead to, or exacerbate, the development of degenerative joint disease in children and adults.
B. Inflammation
  • Further elucidate the mechanisms by which nutrients and inflammatory cytokines are transported among the extracellular matrix, synovial compartment, and bone marrow.
  • Identify and characterize inflammatory factors that act on subchondral bone and synovial tissue, as well as their roles in joint degeneration.
  • Study the role of proinflammatory molecules, including the advanced glycation end products that are associated with obesity and diabetes, in joint degradation.
C. Pain
  • Assess the basic biological processes associated with spinal disorders, and their related pain syndromes.
  • Study the genes and molecular pathways that give rise to painful osteoarthritic joints.
D. Aging and genetic factors
  • Define the role of cellular aging and aging-associated epigenetic changes on the onset and progression of degenerative joint disease.
  • Develop well-characterized, age-appropriate animal models for the study of degenerative joint disease.
  • Investigate the mechanisms of disease in genetically defined subsets of degenerative joint disease.
4. Genetics and genomics

The explosion of information related to genetics and genomics is allowing researchers to understand the development and maintenance of musculoskeletal systems. In the future, a patient’s genetic code may guide predictive and personalized approaches to treating musculoskeletal conditions. Advances in this area allow scientists to better understand the causes of, and develop strategies against, complex diseases. Well-planned and well-executed clinical studies that provide validated phenotypic data for cases and controls to the broad scientific community are of great value. Genome-wide association studies have generated data for many diseases and provide a rich resource for the improved understanding of disease, despite the technical and economic challenges of the approach.

Broad areas of potential research directions include:

A. Genetic defect diseases
  • Continue fundamental research on connective tissue molecules (e.g., collagens, elastins, fibrillin) and their intercellular and extracellular interactions, toward the development of new therapies against heritable diseases of connective tissue, such as Marfan syndrome and Ehlers-Danlos syndrome.
  • Pursue in vivo studies such as quantitative trait loci (QTL) analyses to identify genes that define the properties of cartilage and joints.
  • Study the mechanisms by which gene mutations contribute to musculoskeletal conditions, research that may lead to new treatments or prevention strategies.
B. Genetic predisposition to osteoarthritis
  • Assemble and study large, well-characterized collections of cases and matched controls with post-traumatic osteoarthritis; where possible, adapt existing cohorts to genetic studies.
  • Determine the contribution of gene-gene and gene-environment interactions to the overall genetic influence on disease susceptibility.
  • Investigate the role of genetic influences on disease susceptibility, including genome-wide association strategies to detect multiple genes that contribute to a given phenotype.
  • Use genetically modified mice and new tools for genetic analysis in mice and humans to understand the genes involved in joint degeneration and to develop approaches for treating and preventing disease.
C. Epigenetics
  • Characterize epigenetic modifications that may relate to the development of healthy tissues and chronic diseases of the joint.
  • Explore the possible roles of epigenetic mechanisms in the differential onset and progression of musculoskeletal diseases.

Musculoskeletal Biology and Diseases: Regenerative Medicine and Orthopaedic Implants

1. Research technologies and the environment for regenerative medicine studies

Regenerative medicine—tissue engineering and gene, cell, and pharmacological treatments that restore tissue structure and function—is a multidisciplinary field involving both the life and physical sciences. Developing novel technologies is essential for progress in regenerative medicine. Coordinated and collaborative research efforts will also be necessary to move this field forward.

More testing in animals, especially large-animal models, is needed for bench-to-bedside translation of regenerative medicine research. For example, the development of orthopaedic implants and surgical techniques, as well as the translation of the regeneration of weight-bearing musculoskeletal structures, all specifically require large-animal studies. On the other hand, the NIAMS also encourages research on the development of tissue-engineered, cell-based models that will reduce the cost associated with animal models and lessen the scientific community’s need to use animals in research.

In addition to the examples of model systems listed elsewhere in this plan (see Infrastructure), broad areas of potential research directions include:

A. Enabling technologies
  • Develop and test minimally or non-invasive methods and devices to deliver scaffolds in situ.
  • Investigate new methods for sterilizing and preserving natural and synthetic materials and scaffolds.
  • Facilitate the standardization of tissue culture reagents and protocols, safety procedures, outcome measures, testing and validation of animal models, and evaluation techniques.
  • Promote large-animal studies for use in regenerative medicine research.
B. Molecular and gene-based strategies
  • Design and test methods to deliver molecular or gene-based therapies for repairing bone, cartilage, and connective tissues, and for the treatment and prevention of joint diseases. Of particular interest are in vivo strategies to deliver cells, genes, or biomolecules.
  • Develop and test gene- or protein-based approaches for healing bone fractures, especially large bone defects.
  • Generate methods for site-specific, endogenous gene- and cell-modulation to facilitate integration of engineered tissues.
  • Accelerate the translation of cell-, gene-, and tissue engineering-based strategies into clinical testing by conducting large-animal studies.
C. Multidisciplinary research
  • Develop multidisciplinary research teams with expertise in the life and physical sciences (e.g., developmental biologists working with tissue engineers).
  • Encourage cross-disciplinary discussions on broad issues in regenerative medicine and provide opportunities for cross-training and education for emerging clinician scientists.
2. Cell-based therapies

Understanding the behavior of cells in response to their own environment is critical for developing cell-based strategies to repair or regenerate musculoskeletal tissue. This requires knowledge of cellular processes and the environment in which they exist. Insights into how biological, chemical, and mechanical conditions affect cell behavior, as well as that of the micro-environment and the tissues from which the cells originate, would facilitate progress in this area.

In addition to examples identified under Developmental Biology, above, broad areas of potential research directions include:

A. Cell behavior
  • Describe how cells interact with their local and systemic environments to establish and maintain functional musculoskeletal tissues.
  • Develop methods to control responses and interactions between cells and their local environments.
  • Study the influence of inflammation on regenerative processes.
B. Stem cells
  • Assess the use of iPS cells and embryonic stem cells for musculoskeletal tissue applications.
  • Compare and standardize cell sources to identify promising approaches for advancing tissue engineering and regenerative medicine beyond the laboratory and into the clinic (e.g., adult stem cells from muscle, adipose tissue, or bone marrow vs. differentiated cells such as chondrocytes; adult stem cells vs. embryonic or iPS cells).
  • Develop strategies to recruit and direct endogenous progenitor or stem cells for regeneration.
  • Investigate the influence of stem and progenitor cells on inflammatory and immune responses.
3. Scaffolds and biomaterials for tissue engineering

Successful tissue engineering strategies require biomaterials and scaffolds that support the structural and functional development and maintenance of regenerated or repaired musculoskeletal tissues. Studying the biology of tissue development and organization often informs better biomaterial and scaffold designs. Such materials could be used when regenerating tissues in vitro for subsequent implantation in vivo, as well as in direct in vivo tissue regeneration and repair.

In addition to examples identified under Molecular and Cellular Biology of Cartilage and Connective Tissues, above, broad areas of potential research directions include:

A. Development
  • Design biomaterials and scaffolds that direct the growth, differentiation, and organization of cells, by providing appropriate physical, chemical, and mechanical cues to form functional musculoskeletal tissues.
  • Explore innovative uses of the natural extracellular matrix as biomaterials or scaffolds to provide the structural and mechanical properties appropriate for functional musculoskeletal tissues, and develop biomaterials that mimic or result in functionally superior scaffolds.
  • Test biomaterials and scaffolds for their effects on the host immune system and inflammatory responses.
B. Validation
  • Define functional outcome measures to evaluate tissue- engineered products.
  • Standardize and compare biomaterials and scaffolds to identify those with the most promise for advancing beyond the laboratory and into the clinic.
4. Functional integration

Research into the integration of regenerated or engineered tissues within a host organism must reflect the complex physiological interactions across multiple tissue types. Such systemic interactions include biological signaling processes, vascularization, innervation, and influences from the innate and adaptive immune systems. Preservation of structural and mechanical function, host and graft survival, and safety, is also important.

In addition to examples identified under Research Technologies and Environment for Regenerative Medicine Studies, above, broad areas of potential research directions include:

A. Approaches
  • Develop strategies to integrate engineered tissues with the host, while reducing adverse effects (e.g., immunogenicity, toxicity) and considering the ongoing disease process.
  • Validate and standardize functional outcome measures to determine success.
B. Cell-based models
  • Develop standardized, in vitro systems for testing a proposed intervention’s feasibility, function, and safety in preparation for in vivo studies.
5. Orthopaedic implants

Implants such as total hip and knee replacements have been shown to be effective tools to treat end-stage arthritis that has not responded to non-operative treatment, resulting in improved patient function and quality of life. If an implant fails, however, a patient may need a second surgery that is not likely to be as successful as the initial procedure. The main cause of failure is osteolysis (the disappearance of bone around an implant because of a reaction to microscopic particles from the implant). Numerous research opportunities exist to develop improved biomaterials, tools to better assess implant wear, and increased knowledge of the biology and pathophysiology of osteolysis.

Broad areas of potential research directions include:

A. Implant deterioration and failure
  • Analyze the biologic response to implant wear particles.
  • Characterize the features of wear debris that are most critical in determining the biological response to implant wear particles. Detailed mechanistic studies of the pathogenesis of periprosthetic osteolysis and implant loosening in different joints (e.g., hip, knee, spine) may be useful.
  • Determine the role of the innate and adaptive immune system in the pathogenesis of implant failure.
  • Elucidate the effects of stress shielding on the bony structures (e.g., the acetabulum) that support implants.
  • Establish long-term wear behavior in the spine for conventional biomaterials in comparison with that in the hip and knee.
  • Explain and quantify the phenomena of third body wear (implant debris that become trapped between the two implant surfaces), and design preventive strategies to counter it.
  • Investigate the factors governing implant wear and the host tissue response to wear debris.
  • Pursue clinical and histopathological studies to better understand and diagnose metal hypersensitivity.
  • Understand the role of mechanical factors (e.g., motion and pressure) in the development of implant loosening.
  • Use genome-wide array analyses to understand the genetic risk factors for, and their relevance to, osteolysis.
B. Improved materials
  • Explore the chemistry of interactions between biologic lubricants and implant-bearing surfaces.
  • Improve strength and fatigue resistance of polyethylene without compromising wear and oxidation resistance.
C. Tools for testing
  • Develop methods to better assess the metal-on-metal wear of implants.
  • Measure wear in total knee replacement and in metal-on-metal bearing surfaces for total hip replacement. Automated image recognition software, for example, is one possible tool for such studies.
  • Standardize mechanical testing strategies to assess fracture resistance of new polyethylene formulations.
  • Study the efficacy of Computed tomography (CT) and MRI scanning in assessing the extent of implant osteolysis.

Musculoskeletal Biology and Diseases: Imaging and Biomarkers

1. Biochemical markers

Many musculoskeletal diseases are chronic and have long, variable clinical courses. These conditions take decades to develop and can be difficult to characterize. Biomarkers of disease and responses to treatment are often assessed by measuring biochemical factors in blood or body fluids, or through analyses of genetic biomarkers from tissues or peripheral blood cells. However, for many of these conditions, responses to therapies are difficult to determine. Researchers are beginning to believe that, as with many disorders, a battery of biomarkers may be more useful than a single biomarker when studying these conditions. The box below describes an NIH effort to create a public resource to validate imaging and biochemical biomarkers for osteoarthritis.

Osteoarthritis Initiative (OAI): A limited number of therapies exist for osteoarthritis (OA) treatment. Most only relieve pain and reduce disability; none slows or halts disease progression. One barrier to the development of drugs that block the underlying causes of OA symptoms is the lack of objective and measurable standards for disease progression by which new drugs can be evaluated. To overcome this problem, the NIH—with input from the U.S. Food and Drug Administration—partnered with private sponsors to create the Osteoarthritis Initiative (OAI). When complete, the OAI will provide an unparalleled state-of-the-art database showing both the natural progression of the disease and information on risk factors, joint changes, and outcome measures. All data will be freely available to researchers worldwide, who can develop hypotheses about possible OA biomarkers of disease onset and progression, test their theories, describe the natural history of OA, and investigate factors that influence disease development and severity. Scientists also can use the OAI to identify potential disease targets and to develop tools for measuring clinically meaningful improvements.

Originally, the OAI was slated to receive funding through FY2009, during which time investigators would collect survey, clinical, and image data and biological samples from approximately 4,800 people at baseline, 12-, 24-, 36-, and 48-month time points. NIH has extended the study through FY 2014 to include 72- and 96-month data points.

For further information, see:

OAI page on the NIAMS Web site (


Broad areas of potential research directions include:

A. Identification, qualification, and validation
  • Broaden biomarker investigations to include genetic markers of disease or markers that may predispose individuals to a heightened risk of disease progression, worsening, and severity, or those biomarkers that predict responses to treatments.
  • Conduct basic exploratory studies to identify lead candidate biomarkers.
  • Develop and apply new technologies for the discovery of biomarkers of disease onset, progression, and response to therapy. The orthopaedic community, for example, would benefit from the discovery of biomarkers of implant wear and osteolysis.
  • Identify biomarkers that will be useful for predicting overall outcomes or those in specific subsets of patients. Of particular interest is the use of existing repositories and databases to qualify and validate the biochemical and structural changes associated with onset and progression of osteoarthritis.
  • Study non-invasive biomarkers to facilitate the early diagnosis of musculoskeletal infections and to monitor the treatment of musculoskeletal infections, including those around implanted devices.
B. Resource development and application
  • Create and standardize multiplex arrays that simultaneously measure multiple biomarker candidates in a single sample.
  • Develop imaging technologies and system biology approaches and apply them to the discovery of biomarkers of disease onset, progression, and response to therapy.
  • Produce and assemble resources to assist investigators engaged in biomarker development and validation.
  • Use existing infrastructure, such as databases and clinical cohorts, to move promising biomarkers from the laboratory to the clinic through the application of state-of-the-art statistical, analytical, and computational methods.
2. Biomedical imaging

The broad, innovative use of imaging techniques, in combination with measurements of biochemical markers, could allow the early identification of disease onset, predict disease progression, and enable the direct monitoring of responses to tissue repair and therapeutic interventions. The capability to image early or late changes of disease in end organs becomes increasingly important for characterization of disease status and response to therapy. In addition, despite significant recent advances in medical imaging, many questions remain with regard to the interpretation and application of new technologies aimed at more accurate disease diagnosis and monitoring. The complexity of data analyses may require close collaboration with biostatisticians.

In addition to examples identified under Orthopaedic Implants, above, broad areas of potential research directions include:

A. Imaging methods and osteoarthritis risk factors
  • Apply existing and newly developed imaging technologies when studying disease and identifying possible imaging biomarkers associated with disease onset and progression.
  • Standardize methods for evaluating changes in human joint structure—synovium, cartilage, bone, ligaments, tendons, and meniscus—associated with normal aging. Differentiate these changes from those associated with symptomatic joint diseases like osteoarthritis.
B. Imaging for regenerative medicine
  • Develop real-time, minimally or non-invasive imaging modalities for in vivo monitoring of cell proliferation, differentiation, survival, migration, and integration.
  • Develop real-time, minimally or non-invasive imaging modalities to monitor tissue function, repair, and integration processes in vivo.

Musculoskeletal Biology and Diseases: Clinical Research

1. Behavioral and psychosocial research

Behavioral and psychosocial factors are involved in the onset, course, and outcome of chronic diseases. These factors are central in the experience of symptoms (such as pain and fatigue), disease-related distress, and coping with chronic disease, disability, and, to varying extents, the success of prevention and treatment approaches. Interdisciplinary research that integrates behavioral and biomedical sciences is likely to result in enhanced management of these diseases and reduced disability, and may shed light on the complex mechanisms involved in disease processes.

Broad areas of potential research directions include:

  • Assess the willingness of members of racial and ethnic sub-populations of the United States to undergo total joint replacement.
  • Determine the mechanisms and outcomes of behavioral therapies for treating chronic musculoskeletal conditions and injuries.
  • Develop and validate more accurate and appropriate outcome measures for the study of disability related to musculoskeletal conditions and injuries.
  • Clarify the impact that psychological distress has on recovery after musculoskeletal trauma, and design strategies to prevent or diagnose it.
2. Childhood musculoskeletal conditions

The cost of childhood musculoskeletal conditions is enormous. Although some conditions can be treated with a full restoration to active life, others can result in early death or progressive problems into adulthood. Still others present lifelong challenges to the affected individual, his or her family, and society. Prevention of childhood injury is addressed under Fractures and Skeletal Trauma, below.

Broad areas of potential research directions include:

  • Develop physiologic interventions to correct skeletal deformities and neuromuscular disorders, including cerebral palsy and muscular dystrophies.
  • Study the musculoskeletal implications and complications of rheumatic diseases in children. Examples include growth delay, osteoporosis, and avascular necrosis.
3. Degenerative joint disease

Americans over 65 are the fastest growing segment of the U.S. population, and this group is expected to reach 68 million by 2010. Although degenerative joint diseases affect at least 70 percent of these older Americans, very few, if any, disease-modifying agents exist for people who have osteoarthritis, the most common of these conditions.

Broad areas of potential research directions include:

A. Risk factors
  • Define and stratify risk factors for degenerative joint disease development in individuals and populations. These include body weight, previous joint injury, family history, diet, physical activity, coincident pathology of other tissues and organs, and medication use.
  • Determine the effects of changes in modifiable risk factors on the onset and progression of degenerative joint disease.
  • Develop or modify strategies, including preventive and rehabilitative approaches, to reduce the development of disability and functional limitation associated with the onset and progression of degenerative joint disease.
B. Treatments
  • Explore rehabilitation and physical therapy strategies to reduce risk for impairment from degenerative joint disease progression.
  • Identify and characterize agents and approaches to decrease the disability and pain related to cartilage and connective tissue diseases. Pursue innovative treatment strategies.
  • Investigate strategies to prevent or reverse structural modifications of diseased joints; identify new targets and develop corresponding therapeutic agents.
  • Study the outcomes of treatments of joint injuries to prevent post-traumatic osteoarthritis.
4. Spinal disorders

Many spinal disorders are common, costly, and potentially disabling. Low back pain affects millions of people around the world and has an enormous socioeconomic impact. A frequent cause of disability, low back pain causes workers to lose many days of work each year. Although low back pain constitutes an important public health issue, little is known about its causes. A considerable investment in a study of surgical and non-surgical therapies for common causes of low back pain has yielded important results (see box below). However, much remains to be discovered about strategies to improve the lives of those who are affected by back pain or related disorders.

The Spine Patient Outcomes Research Trial (SPORT) for low back pain: Before SPORT, many people who had chronic low back pain were conflicted about whether to undergo surgery: Some were not sure surgery was worth the risk, while others feared that delaying surgery might cause even more damage. SPORT has demonstrated that, indeed, surgery is better than nonoperative treatments for the three most common causes of severelow back pain: intervertebral disk herniation and lumbar spinal stenosis with or without degenerative spondylolisthesis (the slipping of vertebrae). However, people who have one of these conditions are not subjecting themselves to further harm if they adopt a “wait-and-see” approach before committing to surgery.

The benefits of surgery to correct spinal stenosis, for example, were apparent as early as six weeks after surgery 1, 2. Those patients who had severe slippage and discomfort due to lumbar spinal stenosis with degenerative spondylolisthesis seemed to benefit the most 3. Although people who did not have surgery reported some improvement two years into the study, those who had surgery seemed to be doing considerably better1, 2. Additionally, SPORT showed that combining two surgical procedures—decompressive laminectomy and fusion—did not help patients who had lumbar spinal stenosis without degenerative spondylolisthesis any more than decompressive laminectomy alone4. The findings regarding intervertebral disk herniation were equally meaningful. Two years after surgery, patients who had surgery for a herniated upper lumbar disk felt significantly better than those who had had a lower disk repaired5. The benefits persisted through the four-year follow-up study6. Although more costly than approaches such as medications and physical therapy, lumbar diskectomy is a cost-effective treatment7.


1 Weinstein JN, et al. N Engl J Med. 2007. PMID: 17538085
2 Weinstein JN, et al. N Engl J Med. 2008. PMID: 18287602
3 Pearson AM, et al. Spine. 2008. PMID: 19050582
4 Tosteson AN, et al. Ann Intern Med. 2008. PMID: 19075203
5 Lurie JD, et al. J Bone Joint Surg Am. 2008. PMID: 18762639
6 Weinstein JN, et al. Spine. 2008. PMID: 19018250
7 Tosteson AN, et al. Spine. 2008. PMID: 18777603


In addition to examples noted under Orthopaedic Implants, above, broad areas of potential research directions include:

  • Develop and evaluate new treatment methods and technologies for degenerative disk disease, including the use of an artificial disk and nucleus, and the use of regenerative medicine techniques to reverse the process of disk degeneration.
  • Pursue clinical studies to address the management of spinal disorders that are common and costly, and for which consensus regarding preferred treatment is lacking.
  • Study the efficacy and effectiveness of emerging technologies in treating spinal disorders.
5. Implant science and devices

As described under Orthopaedic Implants, above, implants for total hip and knee replacements are effective treatments for people who have end-stage arthritis. However, a potential complication from these procedures is musculoskeletal infection, which can be costly, life-threatening, and difficult to diagnose. Although infection at the site of a total joint replacement is rare, it can be devastating and require lengthy hospitalization. In addition, revision or salvage procedures are not likely to be as successful as the initial joint replacement.

In addition to examples noted under Orthopaedic Implants and Biochemical Markers, above, broad areas of potential research directions include:

A. Outcomes
  • Analyze outcomes of revision total knee and hip replacements. Such studies could be useful for identifying grafting techniques that lead to well-fixed implants, defining the roles of bone and synthetic graft materials, and quantifying graft incorporation and bone resorption.
  • Develop and implement strategies to prevent implant-related musculoskeletal infections.
  • Investigate the effects of anabolic agents post-operatively to see whether they can significantly increase osteointegration of the implant and decrease subsequent loosening.
  • Test the long-term biocompatibility and wear properties of alternative bearing surfaces.
B. Techniques and timing
  • Assess the impact of small incision, minimally invasive surgical approaches, and robotic surgery on functional outcomes, complications, and revision rates.
  • Develop and validate pre- and post-operative rehabilitation strategies, especially for hip and knee replacement.
  • Standardize the criteria for determining the therapeutic effects of non-surgical interventions (such as drugs or rehabilitation strategies) to prevent or treat implant osteolysis, to enable comparison of interventions across different studies.
  • Study the clinical and economic impact of an earlier diagnosis of implant osteolysis.
6. Fractures and skeletal trauma

In addition to the health-care expenditures, injuries associated with fractures and skeletal trauma cost billions of dollars in terms of lost employment and sometimes lifetime disability. Trauma is the leading cause of death after the first year of life; it exceeds all other causes of childhood death combined. Treatment of patients who suffer fractures in conjunction with trauma to other organ systems (e.g., traumatic brain injury) is a challenge in musculoskeletal care. After injury prevention, methods to reduce complications, disability, and mortality are paramount. Further refinement of operative and non-operative techniques and rehabilitation after fractures or skeletal trauma will improve patient outcomes, enhance the lives of patients and their caregivers, and facilitate their return to the workforce.

In addition to the example under Behavioral and Psychosocial Research, above, broad areas of potential research directions include:

A. Prevention
  • Elucidate the mechanical forces that contribute to/cause joint injury and the consequences of cumulative trauma disorders of soft tissues. Such studies will be useful for preventing injuries and developing protective devices for sports and occupational activities.
B. Management
  • Develop and validate measures that better assess fracture healing.
  • Enhance strategies to recognize and treat combined injuries, especially as they relate to the timing and type of surgery in multiple trauma patients, or those suffering head injury, chest injury, or shock.
  • Further establish the outcomes and cost-effectiveness of treatments for specific fractures and injuries.
  • Improve surgical strategies for correcting skeletal injuries such as compartment syndromes, fractures in older people, and mangled extremities.
  • Test methods to diagnose and treat injuries to and around growth plates, to prevent growth disturbances.
C. Study design
  • Implement strategies to standardize clinical studies of interventions that influence fracture healing, using both objective and subjective parameters.
7. Sports and fitness

Fitness is associated with good health and a sense of well-being. Numerous studies have shown the beneficial effects of exercise in disease prevention, yet one of the problematic effects of exercise is injury. Musculoskeletal soft tissues are vulnerable to injury and damage as the result of overuse and/or trauma. These injuries are often life-altering. In addition, the cartilage loss that leads to joint degeneration is generally slow and progressive with age.

In addition to examples noted under Degenerative Joint Disease and Fractures and Skeletal Trauma, above, broad areas of potential research directions include:

A. Physical activity requirements
  • Better understand how particular fitness requirements vary with gender, age, and conditions that limit mobility. Such knowledge is important for efforts to encourage physical fitness and promote health.
B. Injury prevention
  • Characterize gender differences in ultra-high performance sports as the groundwork for focused programs to prevent disorders commonly seen in these athletes.
C. Treatment and rehabilitation
  • Apply physical medicine and rehabilitative strategies to soft-tissue injuries, to restore maximal function.
  • Determine the type and level of exercise effective for minimizing the progression of specific diseases and promoting restoration of musculoskeletal function. Such knowledge could translate into "exercise prescriptions."


The NIAMS Long-Range Plan for FY 2010-2014 underscores the Institute’s commitment to identifying and responding to promising scientific opportunities and emerging public health needs across the spectrum of its research portfolio. The Institute is grateful to the hundreds of investigators, health-care providers, and patient advocates who contributed to the NIAMS extramural planning process for the benefit of the American public.

Investigator-initiated research project grants and research conducted by new scientists remain the Institute’s highest priorities, and the NIAMS will continue to direct its efforts toward enabling or complementing investigator-initiated activities under this plan.

The NIAMS is committed to maintaining a balanced portfolio of the highest quality research that reflects the variety of scientific opportunities to improve public health. The NIAMS will continue to establish and maintain partnerships with other NIH Institutes and Centers, Federal agencies, private foundations, and private-sector organizations to advance the understanding, diagnosis, treatment, and, ultimately, prevention of arthritis and musculoskeletal and skin diseases.

The ingenuity and creativity of the NIAMS grantee population leads us in new, exciting, and productive directions toward achieving the Institute’s mission. Paramount to everything we do is the aim to improve the quality of life for Americans affected by costly and often chronic and disabling diseases of bones, muscles, joints, and skin.


Appendix 1: Overview of the Development Process

The overall concept for the NIAMS FY Long-Range Plan for 2010-2014 was presented for clearance at the September 2008 NIAMS Advisory Council meeting. As part of this process, it was decided that existing plans on lupus ( and muscular dystrophy ( would continue to serve as companion pieces to the NIAMS Long-Range Plan for FY 2010-2014, since the needs and opportunities presented in these documents are of particular interest to the NIAMS and other NIH components.

Following Council approval, the formal process for developing the plan began in the fall of 2008 with a public Request for Comments, which encouraged feedback from researchers, professional and patient advocacy organizations, health-care providers, and patients and their families. A series of questions was posted on the NIAMS Web site for 30 days. Respondents were asked to provide input on the following:

  • the top three recent research advances in their area(s) of interest,
  • the most promising areas of science,
  • the most pressing scientific and training needs,
  • the greatest challenges to research progress and potential solutions,
  • and existing gaps in training.

Information obtained from the public Request for Comments was used to shape a series of roundtable meetings that were hosted by the NIAMS during November-December 2008, and focused on the five main areas of the plan: Arthritis and Rheumatic Diseases, Skin Biology and Diseases, Bone Biology and Diseases, Muscle Biology and Diseases, and Musculoskeletal Biology and Diseases. Based on feedback gathered during these meetings, four cross-cutting areas were also identified: Health Disparities, Infrastructure, Training and Career Development, and Information Dissemination. Summaries of these meetings are available on the NIAMS Web site ( In addition to NIAMS scientific staff, roundtable participants included members of the research community and lay representatives. Before the meetings, NIAMS staff members developed and disseminated appropriate background and guidance documents, to prepare participants for the discussions. Participants were encouraged to gather and share the views of the broader research community by consulting a diverse set of colleagues in advance.

Updates on the progress of the development of the NIAMS Long-Range Plan for FY 2010-2014 were provided at the February and June 2009 Advisory Council meetings, and the draft plan was presented in September 2009. Additionally, in November 2009, the Institute sponsored an informational meeting that provided an opportunity for input from representatives of the NIAMS Coalition, a group of professional and voluntary organizations interested in the NIAMS mission areas. The Institute was particularly interested in feedback about needs and opportunities as seen from the patient perspective. NIAMS staff members also encouraged participants to disseminate the draft plan to their constituencies in order to facilitate comprehensive input during the final public comment period.

The draft plan was posted on the NIAMS Web site for 30 days and responses were collected through a standardized Web-based form. The online posting was announced to both the scientific and lay communities of interest to the NIAMS. Institute staff members also took into consideration comments received directly by email or traditional mail. All comments were reviewed carefully and incorporated into the document, as appropriate.

After final clearance by the NIAMS Advisory Council in February 2010, the final version of the NIAMS Long-Range Plan for FY 2010-2014 was posted on the Institute’s public Web site and widely disseminated to NIAMS communities. Staff also developed an easy-to-read tri-fold brochure accessible to a broad audience that provides a brief overview of the plan and highlights its main objectives.

Appendix 2: Development Timeline for the NIAMS Long-Range Plan: Fiscal Years 2010 - 2014

2008 September/October Request for Comments posted on NIAMS Web site for public input on key areas of need and opportunity (pre-development phase)
November/December Roundtable discussions with outside experts and NIAMS staff
2009 February Update to NIAMS Advisory Council on the development of the plan
June Update to NIAMS Advisory Council on the development of the plan
September Draft plan presented to the NIAMS Advisory Council for review and input
November Draft plan presented at a meeting of NIAMS Coalition representatives
December Draft plan and a Request for Comments posted on NIAMS Web site to gather public input
2010 December/January Review of public comments on draft plan and updates incorporated, as appropriate
February Final plan presented to the NIAMS Advisory Council and posted on Institute's Web site


Appendix 3: Roundtable Summaries

In 2008, the NIAMS began developing a new long-range plan for fiscal years 2010-2014 to provide a broad outline of opportunities and needs related to the understanding, diagnosis, treatment, and ultimately, prevention of diseases within the Institute's mission areas. As part of this process, the NIAMS hosted a series of roundtable discussions to get input and guidance from the scientific community about areas of research to include in the new plan. The roundtables were organized around five tissue- and disease-specific themes:

  • Arthritis and Rheumatic Diseases
  • Bone Biology and Diseases
  • Muscle Biology and Diseases
  • Musculoskeletal Biology and Diseases
  • Skin Biology and Diseases

Meeting participants were asked to consider the following questions:

  • What have been the top three advances within the past five years?
  • What are the three most promising areas of science?
  • What are the three most pressing scientific needs?
  • What are the three greatest challenges, other than workforce issues, to research progress? What are the potential options for overcoming these challenges?
  • What gaps in training have delayed progress in critical research areas?
  • What innovative, creative approaches are needed to transform the understanding of health disparities?

Discussion at each roundtable expanded on the feedback compiled by its participants, as well as that which members of the larger community submitted via a Web-based Request for Comments. Brief meeting summaries are available at