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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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References

  1. Zaidi, M. Skeletal remodeling in health and disease. Nat. Med. 13, 791–801 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Hill, P.A. Bone remodelling. Br. J. Orthod. 25, 101–107 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Janssens, K. et al. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat. Genet. 26, 273–275 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Kinoshita, A. et al. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat. Genet. 26, 19–20 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Hecht, J.T. et al. Evidence for locus heterogeneity in the Camurati-Engelmann (DPD1) syndrome. Clin. Genet. 59, 198–200 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Oreffo, R.O., Mundy, G.R., Seyedin, S.M. & Bonewald, L.F. Activation of the bone-derived latent TGF beta complex by isolated osteoclasts. Biochem. Biophys. Res. Commun. 158, 817–823 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Mundy, G.R. Peptides and growth regulatory factors in bone. Rheum. Dis. Clin. North Am. 20, 577–588 (1994).

    CAS  PubMed  Google Scholar 

  8. Martin, T.J., Allan, E.H. & Fukumoto, S. The plasminogen-activator and inhibitor system in bone remodeling. Growth Regul. 3, 209–214 (1993).

    CAS  PubMed  Google Scholar 

  9. Hill, P.A., Tumber, A. & Meikle, M.C. Multiple extracellular signals promote osteoblast survival and apoptosis. Endocrinology 138, 3849–3858 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Pfeilschifter, J. et al. Chemotactic response of osteoblast-like cells to transforming growth-factor-beta. J. Bone Miner. Res. 5, 825–830 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Linkhart, T.A., Mohan, S. & Baylink, D.J. Growth factors for bone growth and repair: IGF, TGF beta and BMP. Bone 19, 1S–12S (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Hughes, F.J., Aubin, J.E. & Heersche, J.N.M. Differential chemotactic responses of different populations of fetal-rat calvaria cells to platelet-derived growth-factor and transforming growth-factor-beta. Bone Miner. 19, 63–74 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Bismar, H. et al. Transforming growth factor beta (TGF-beta) levels in the conditioned media of human bone cells: relationship to donor age, bone volume, and concentration of TGF-beta in human bone matrix in vivo. Bone 24, 565–569 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Roberts, A.B., Frolik, C.A., Anzano, M.A. & Sporn, M.B. Transforming growth factors from neoplastic and nonneoplastic tissues. Fed. Proc. 42, 2621–2626 (1983).

    CAS  PubMed  Google Scholar 

  15. Seyedin, S.M., Thomas, T.C., Thompson, A.Y., Rosen, D.M. & Piez, K.A. Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. Proc. Natl. Acad. Sci. USA 82, 2267–2271 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dallas, S.L. et al. Characterization and autoregulation of latent transforming growth-factor-beta (TGF-beta) complexes in osteoblast-like cell-lines - production of a latent complex lacking the latent TGF-beta-binding protein. J. Biol. Chem. 269, 6815–6821 (1994).

    CAS  PubMed  Google Scholar 

  17. Gentry, L.E., Lioubin, M.N., Purchio, A.F. & Marquardt, H. Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol. Cell. Biol. 8, 4162–4168 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pfeilschifter, J., Bonewald, L. & Mundy, G.R. Characterization of the latent transforming growth factor beta complex in bone. J. Bone Miner. Res. 5, 49–58 (1990).

    Article  CAS  PubMed  Google Scholar 

  19. Pedrozo, H.A. et al. Potential mechanisms for the plasmin-mediated release and activation of latent transforming growth factor-beta 1 from the extracellular matrix of growth plate chondrocytes. Endocrinology 140, 5806–5816 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Janssens, K., ten Dijke, P., Janssens, S. & Van Hul, W. Transforming growth factor-beta 1 to the bone. Endocr. Rev. 26, 743–774 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Jian, H. et al. Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta 1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev. 20, 666–674 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Erlebacher, A., Filvaroff, E.H., Ye, J.Q. & Derynck, R. Osteoblastic responses to TGF-beta during bone remodeling. Mol. Biol. Cell 9, 1903–1918 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Filvaroff, E. et al. Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass. Development 126, 4267–4279 (1999).

    CAS  PubMed  Google Scholar 

  24. Janssens, K. et al. Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment. J. Med. Genet. 43, 1–11 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Janssens, K., ten Dijke, P., Ralston, S.H., Bergmann, C. & Van Hul, W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J. Biol. Chem. 278, 7718–7724 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Saito, T. et al. Domain-specific mutations of a transforming growth factor (TGF)-beta 1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-beta 1. J. Biol. Chem. 276, 11469–11472 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Prockop, D.J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71–74 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Caplan, A.I. Mesenchymal stem-cells. J. Orthop. Res. 9, 641–650 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Dennis, J.E., Carbillet, J.P., Caplan, A.I. & Charbord, P. The STRO-1+ marrow cell population is multipotential. Cells Tissues Organs 170, 73–82 (2002).

    Article  PubMed  Google Scholar 

  30. Gronthos, S., Graves, S.E., Ohta, S. & Simmons, P.J. The Stro-1+ fraction of adult human bone-marrow contains the osteogenic precursors. Blood 84, 4164–4173 (1994).

    CAS  PubMed  Google Scholar 

  31. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Meirelles, L.S. & Nardi, N.B. Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization. Br. J. Haematol. 123, 702–711 (2003).

    Article  Google Scholar 

  33. Leucht, P. et al. Effect of mechanical stimuli on skeletal regeneration around implants. Bone 40, 919–930 (2007).

    Article  PubMed  Google Scholar 

  34. Caplan, A.I. Mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng. 11, 1198–1211 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Horwitz, E.M. et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med. 5, 309–313 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Horwitz, E.M. et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc. Natl. Acad. Sci. USA 99, 8932–8937 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mirmalek-Sani, S.H. et al. Characterization and multipotentiality of human fetal femur-derived cells: implications for skeletal tissue regeneration. Stem Cells 24, 1042–1053 (2006).

    Article  PubMed  Google Scholar 

  38. Canalis, E., Economides, A.N. & Gazzerro, E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr. Rev. 24, 218–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Ozaki, Y. et al. Comprehensive analysis of chemotactic factors for bone marrow mesenchymal stem cells. Stem Cells Dev. 16, 119–130 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Maeda, S., Hayashi, M., Komiya, S., Imamura, T. & Miyazono, K. Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells. EMBO J. 23, 552–563 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kulkarni, A.B. et al. Transforming growth factor-beta-1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Geiser, A.G. et al. Decreased bone mass and bone elasticity in mice lacking the transforming growth factor-beta 1 gene. Bone 23, 87–93 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Atti, E. et al. Effects of transforming growth factor-beta deficiency on bone development: a Fourier transform-infrared imaging analysis. Bone 31, 675–684 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Shinkai, Y. et al. Rag-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Engle, S.J. et al. Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res. 62, 6362–6366 (2002).

    CAS  PubMed  Google Scholar 

  46. Massagué, J. TGF-beta signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).

    Article  PubMed  Google Scholar 

  47. Attisano, L. & Wrana, J.L. Signal transduction by the TGF-beta superfamily. Science 296, 1646–1647 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. DaCosta Byfield, S., Major, C., Laping, N.J. & Roberts, A.B. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol. Pharmacol. 65, 744–752 (2004).

    Article  PubMed  Google Scholar 

  49. Hayashi, H. et al. The MAD-related protein Smad7 associates with the TGF beta receptor and functions as an antagonist of TGF beta signaling. Cell 89, 1165–1173 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Yang, X., Li, C.L., Herrera, P.L. & Deng, C.X. Generation of Smad4/Dpc4 conditional knockout mice. Genesis 32, 80–81 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Engler, A.J., Sen, S., Sweeney, H.L. & Discher, D.E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Zink, A.R. et al. Evidence for a 7000-year-old case of primary hyperparathyroidism. JAMA 293, 40–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Roodman, G.D. & Windle, J.J. Paget disease of bone. J. Clin. Invest. 115, 200–208 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Surks, M.I. et al. Subclinical thyroid disease - Scientific review and guidelines for diagnosis and management. JAMA 291, 228–238 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Friedenstein, A.J., Chailakhyan, R.K. & Gerasimov, U.V. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 20, 263–272 (1987).

    CAS  PubMed  Google Scholar 

  56. Owen, M. & Friedenstein, A.J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136, 42–60 (1988).

    CAS  PubMed  Google Scholar 

  57. Friedenstein, A.J. et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp. Hematol. 2, 83–92 (1974).

    CAS  PubMed  Google Scholar 

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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.

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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.

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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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