TGF-β1–induced migration of bone mesenchymal stem cells couples bone resorption with formation

Abstract

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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Figure 1: Osteoclastic bone resorption–conditioned medium (BRCM) induces migration of BMSCs.
Figure 2: Tgfb1−/−Rag2−/− mice show lower bone mass.
Figure 3: Migration of implanted BMSCs to bone resorptive sites is lower in Tgfb1−/− mice.
Figure 4: SMAD signaling pathway mediates TGF-β1–induced migration of BMSCs.
Figure 5: Bone resorption is uncoupled from bone formation in CED transgenic mice.
Figure 6: TβRI inhibitor partially rescues uncoupled bone remodeling in TGFB1-CED mice.

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Acknowledgements

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.

Author information

Y.T. and X.W. performed the majority of the experiments, analyzed data and prepared the manuscript. W.L. maintained mice and collected tissue samples. L.P. helped with the in vitro Transwell migration assay. C.W. helped with μCT analyses. Z.S. helped with the in vitro bone resorption assay. L.Z. assisted with in vivo experiments. T.R.N. helped with X-ray analyses. X.P., J.H., X.F. and W.V.H. provided suggestions for the project. M.W. prepared the manuscript. X.C. supervised the project and wrote most of the manuscript.

Correspondence to Xu Cao.

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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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