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Genomics in Action: Yingzi Yang, Ph.D.

Using Genomics to Improve the Treatment of Bone Disorders

By Jim Swyers, NHGRI Staff Writer

Bone disorders such as osteoarthritis and osteoporosis are among the common, major health problems facing older people today. Over the years, researchers have developed a number of innovative surgical procedures, drugs and other approaches aimed at treating these debilitating conditions. There still are no cures, however, and the regeneration of bone and cartilage remains an unachieved aspiration. Now, however, a team from the National Human Genome Research Institute (NHGRI) is using its expertise in developmental genetics to move medical science one step closer to that goal.

The precursor cells of cartilage and bone are chondrocytes and osteoblasts, respectively. In developing embryos and adult bone marrow, both chondrocytes and osteoblasts arise from a type of cell referred to as mesenchymal progenitor cells. In their latest work published in the May issue of the journal Developmental Cell, NHGRI's Yingzi Yang, Ph.D., and her colleagues shed light on the genetic mechanisms involved in determining why one mesenchymal progenitor cell becomes a chondrocyte and gives rise to cartilage, while another becomes an osteoblast and goes on to build bone.

"We believe that studying the genetics of mesenchymal progenitor cell differentiation will lead to significantly better therapeutic approaches, and may pave the way for the selective repair of cartilage or bone damage," said Dr. Yang, adding that her group's studies may have implications for a number of other conditions, including cancer.

In the United States, 10 million people have osteoporosis and 18 million more have low bone mass, placing them at increased risk for this disease. Osteoporosis, which literally means "porous bones," occurs when the holes in the bone become bigger, making it fragile and liable to break easily. Bone is alive and constantly changing. Worn-out bone is broken down by cells called osteoclasts and replaced by bone-building cells, called osteoblasts. This process of renewal is called bone turnover. In osteoporosis, bone turnover is either hampered or nonexistent.

In contrast to osteoporosis, osteoarthritis affects cartilage, the tough, elastic tissue that normally cushions the joints. As cartilage gradually breaks down and wears away, the bones of the joint rub together, causing pain, swelling and loss of motion. More than 20 million people in the United States have the disease, most of them over 65. However, osteoarthritis is increasing among younger people, arising primarily from sports- or work-related joint injuries.

Dr. Yang, who is head of the Developmental Genetics Section of the Genetic Disease Research Branch in NHGRI's Division of Intramural Research, became interested in bone and cartilage conditions because she studies limb and skeletal development in vertebrate animals. In particular, she concentrates on two groups of signaling molecules, called Wnt and Hedgehog, that play important roles in guiding the formation of many organs and tissues in the developing embryo. Her goal is to understand precisely how these signaling pathways act and interact with each other, as well as with other signaling molecules involved in regulating development.

The recent findings by Dr. Yang and her colleagues indicate that Wnt signaling may act as a "molecular switch" that determines whether mesenchymal progenitor cells develop into osteoblasts or chondrocytes. In their paper in Developmental Cell, the NHGRI researchers reported that mouse embryos that were exposed to higher than normal levels of Wnt signaling had more osteoblast formation and far less chondrocyte formation than normal mouse embryos. Conversely, when the researchers inactivated the gene that codes for β-catenin, which is a protein required for the transduction of Wnt signaling, significantly more chondrocytes formed in mouse embryos at the expense of osteoblast formation. In other words, increased Wnt signaling appears to promote bone formation in vertebrates, while decreased Wnt signaling favors the formation of cartilage.

Furthermore, Dr. Yang's group demonstrated that inactivation of β-catenin in mesenchymal progenitor cells grown in the test tube, or in vitro, caused chondrocytes to form under conditions that normally allow the production of only osteoblasts. This means that it may some day be possible for medical researchers to use molecular signals to direct mesenchymal progenitor cells to develop into either bone or cartilage precursor cells, depending on which cell type needs to be regenerated in a particular patient.

Previously, Dr. Yang's group demonstrated in animal models that the Wnt/β-catenin signaling is both necessary and sufficient for the formation of knees, elbows and other synovial joints, which are complex joints lubricated with a clear liquid called synovial fluid. This fluid works in conjunction with pads of fat to cushion the joint and also helps to maintain the cartilage around the joint.

Based on their findings, the NHGRI laboratory is attempting to create new mouse models for osteoporosis and osteoarthritis. Their strategy involves genetically manipulating the Wnt/β-catenin pathway in mice and then studying the effects on synovial joint maintenance to see to what extent the animals' physical traits and symptoms resemble that of humans with osteoporosis and osteoarthritis. If a close resemblance is found, the mice could be used to identify possible therapeutic targets and test the efficiency of new strategies for treating and preventing these diseases.

Another major focus of Dr. Yang's group is studying Wnt signaling in other tissues. Mesenchymal progenitor cells have the potential to develop into cells that produce not only cartilage and bone, but also the fat, tendon and muscle tissues that make up many different types of organs throughout the body. Specifically, Dr. Yang and her colleagues are studying the role of the Wnt pathway in the healthy development and regeneration of the liver. They are also exploring how disruption of the Wnt pathway may contribute to the development and progression of liver cancer. A related project involves studying a more newly discovered "non-canonical" signaling pathway involving Wnt and calcium, which some evidence suggests may actually serve to suppress cancer.

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Last Updated: March 13, 2012