Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have discovered how a protein called transforming growth factor-β1 (TGF-β1) links bone formation with bone resorption, two processes that must work in concert to remodel healthy bone. Their findings were published in the July 2009 issue of Nature Medicine.

Bone is constantly remodeling itself in a cycle where old bone is removed, or resorbed, and new bone forms in its place. During the resorption part of this cycle, bone cells called osteoclasts break down old 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. But sometimes this coupling process is impaired, and the two stages don't keep pace with one another — as in osteoporosis and Paget's disease of bone.

Scientists have suspected that a molecule released by the bone matrix during resorption recruits bone mesenchymal stem cells (BMSCs) — precursor cells with the ability to become osteoblasts and a variety of other cell types — to bone sites where resorption is occurring and, once there, to differentiate into bone-building osteoblasts.

Hoping to find that molecule, Xu Cao, Ph.D., the study's senior author, and a team of researchers at the University of Alabama at Birmingham (the team has since relocated to Johns Hopkins University) cultured osteoclasts with bone slices, creating a test-tube version of a bone-resorption environment, one that would be easier to study than bone resorption in whole animals. They reasoned that, if the hypothesis was correct, the bone should release the unknown molecule into the medium. The team found that osteoclasts did release molecules that attract BMSCs migration and, by testing a series of possible candidate molecules, they found that the release of TGF-β1 during resorption was the critical factor triggering that migration.

To confirm their findings, the researchers studied mice deficient in TGF-β1 and found that, as expected, BMSCs failed to migrate to bone resorption sites when the TGF-β1 trigger was absent. To study the consequences of excessive TGF-β1, they used a mouse model of Camurati-Engelmann disease (CED), a rare bone coupling disorder that produces active TGF-β1 throughout bone instead of only at resorption sites. They found that BMSCs also failed to migrate to resorption sites, and osteoclasts and osteoblasts clustered at separate areas. More importantly, the researchers found that when they injected a molecule that inhibited TGF-β1 function into the CED mice, they were able to partially correct the defects.

Most bone disease therapies today target either bone formation or bone resorption, not the bone remodeling cycle as a whole. The research team's discovery of the role of TGF-β1 in the cycle is exciting because it offers researchers a new target that might someday yield therapies with more balanced effects on bone.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the 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 NIAMS, call the information clearinghouse at 301-495-4484 or 877-22-NIAMS (free call) or visit the NIAMS Web site at

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Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, Zhao L, Nagy TR, Peng X, Hu J, Feng X, Van Hul W, Wan M, Cao X. TGF-β1induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nature Medicine 2009 July;15(7):757-65.

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