January 1, 2011


Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have described, for the first time, in a recent issue of the Journal of Clinical Investigation, how a cell-signaling protein called Cdc42 plays an important role in the formation and activity of bone-breakdown cells called osteoclasts. Their study in mice demonstrated that deactivating Cdc42 in these cells increases bone mass, making it a potential therapeutic target for osteoporosis researchers.

Bone is constantly remodeling itself in response to everyday stresses and damage in a cycle where old, damaged bone is removed, or resorbed, and new bone forms in its place. During the resorption part of this cycle, osteoclast cells break down old, damaged bone and clear it away. During bone formation, cells called osteoblasts lay down new bone to replace the old bone.

In healthy adults, formation and resorption are synchronized so that new bone replaces old bone in the right quantity, at the right time, and in the right place. When bone resorption outpaces formation, the bone disease osteoporosis can result.

Previous studies on bone resorption led the research team, headed by Haibo Zhao, M.D., Ph.D., of the Washington University School of Medicine in St. Louis, to suspect that Cdc42 helps regulate osteoclasts. They predicted that they would find that Cdc42 is involved in certain osteoclast activities.

In fact, they found that Cdc42 influences not only osteoclast cell activity, but the number of cells. Deleting the gene for Cdc42 reduced the number of osteoclasts by lowering the mature cells’ lifespan, as well as decreasing the proliferation and maturation rate of osteoclast precursor cells (cells that have the capacity to transform into osteoclasts). Osteoclast bone resorption activities were also affected because Cdc42 regulates multiple steps involved in formation of a specialized cellular structure called an actin ring, which enables the osteoclast to break down bone locally.

Furthermore, the team showed that Cdc42-deficient mice that underwent surgical removal of their ovaries – an animal model that simulates bone loss after menopause in women – were protected from bone loss, despite losing the bone-protecting effects of the estrogen produced by the ovaries.

The researchers say they hope their results will lead to strategies for targeting Cdc42 that might result in new therapies for treating bone loss. They are currently focusing on identifying other molecules that regulate Cdc42 in osteoclasts, with the goal of developing osteoporosis treatment.


The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), 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. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at https://www.niams.nih.gov.

Ito Y, Teitelbaum SL, Zou W, Zheng Y, Johnson JF, Chappel J, Ross FP, Zhao H. Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization. J Clin Invest. 2010 Jun 1;120(6):1981-93. doi: 10.1172/JCI39650. Epub 2010 May 24.

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