Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-β1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-β1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-β1 in the bone marrow. Treatment with a TGF-β type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-β1 functions to couple bone resorption and formation, modulation of TGF-β1 activity could be an effective treatment for bone remodeling diseases.
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The authors thank F. Hunter and T. Clemens for critical review and discussion of the manuscript and H.L. Moses (Vanderbilt University), C. Deng (US National Institutes of Health), J. Murphy-Ullrich (University of Alabama at Birmingham) and W. Xiong (Medical College of Georgia) for reagents. We thank the UAB Center for Metabolic Bone Disease Cores for mouse phenotyping, histomorphometry and molecular analyses. This research was supported by US National Institutes of Health grants AR 053973 and DK057501.
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Tang, Y., Wu, X., Lei, W. et al. TGF-β1–induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15, 757–765 (2009). https://doi.org/10.1038/nm.1979
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