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BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing


Adult bones have a notable regenerative capacity. Over 40 years ago, an intrinsic activity capable of initiating this reparative response was found to reside within bone itself, and the term bone morphogenetic protein1 (BMP) was coined to describe the molecules responsible for it. A family of BMP proteins was subsequently identified2,3,4, but no individual BMP has been shown to be the initiator of the endogenous bone repair response. Here we demonstrate that BMP2 is a necessary component of the signaling cascade that governs fracture repair. Mice lacking the ability to produce BMP2 in their limb bones have spontaneous fractures that do not resolve with time. In fact, in bones lacking BMP2, the earliest steps of fracture healing seem to be blocked. Although other osteogenic stimuli are still present in the limb skeleton of BMP2-deficient mice, they cannot compensate for the absence of BMP2. Collectively, our results identify BMP2 as an endogenous mediator necessary for fracture repair.

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Figure 1: Bone formation occurs in the absence of BMP2.
Figure 2: Postnatal bone phenotype in mice lacking BMP2.
Figure 3: Loss of BMP2 leads to loss of fracture healing.
Figure 4: Molecular analysis of repair tissue in Bmp2 mutants.
Figure 5: The initial stages of fracture repair are blocked in the absence of BMP2.

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  1. Urist, M.R. Bone: formation by autoinduction. Science 150, 893–899 (1965).

    Article  CAS  Google Scholar 

  2. Wozney, J.M. et al. Novel regulators of bone formation: molecular clones and activities. Science 242, 1528–1534 (1988).

    Article  CAS  Google Scholar 

  3. Ozkaynak, E. et al. OP-1 cDNA encodes an osteogenic protein in the TGF-β family. EMBO J. 9, 2085–2093 (1990).

    Article  CAS  Google Scholar 

  4. Celeste, A.J. et al. Identification of transforming growth factor β family members present in bone-inductive protein purified from bovine bone. Proc. Natl. Acad. Sci. USA 87, 9843–9847 (1990).

    Article  CAS  Google Scholar 

  5. Yasko, A.W. et al. The healing of segmental bone defects, induced by recombinant human bone morphogenetic protein (rhBMP-2): a radiographic, histological, and biomechanical study in rats. J. Bone Joint Surg. Am. 74, 659–670 (1992).

    Article  CAS  Google Scholar 

  6. Govender, S. et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled randomized study of four hundred and fifty patients. J. Bone Joint Surg. Am. 84-A, 2123–2134 (2002).

    Article  Google Scholar 

  7. Bertone, A.L. et al. Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model. J. Orthop. Res. 22, 1261–1270 (2004).

    Article  CAS  Google Scholar 

  8. Cook, S.D. et al. Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin. Orthop. 301, 302–312 (1994).

    Google Scholar 

  9. Logan, M. et al. Expression of Cre recombinase in the developing mouse limb bud driven by a Prx1 enhancer. Genesis 33, 77–80 (2002).

    Article  CAS  Google Scholar 

  10. Zhang, H. & Bradley, A. Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122, 2977–2986 (1996).

    CAS  PubMed  Google Scholar 

  11. Lyons, K.M. et al. Colocalization of BMP7 and BMP2 RNAs suggests that these factors cooperatively mediate tissue interactions during murine development. Mech. Dev. 50, 71–83 (1995).

    Article  CAS  Google Scholar 

  12. Solloway, M.J. et al. Mice lacking Bmp6 function. Dev. Genet. 22, 321–339 (1998).

    Article  CAS  Google Scholar 

  13. Katagiri, T. et al. Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice. Dev. Genet. 22, 340–348 (1998).

    Article  CAS  Google Scholar 

  14. Rountree, R.B. et al. BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLoS Biol. 2, e355 (2004).

    Article  Google Scholar 

  15. Wu, X-B. et al. Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. J. Clin. Invest. 112, 924–934 (2003).

    Article  CAS  Google Scholar 

  16. Devlin, R.D. et al. Skeletal overexpression of noggin results in osteopenia and reduced bone formation. Endocrinology 144, 1972–1978 (2003).

    Article  CAS  Google Scholar 

  17. Gazzerro, E. et al. Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Endocrinology 146, 655–665 (2005).

    Article  CAS  Google Scholar 

  18. Bonnarens, F. & Einhorn, T.A. Production of a standard closed fracture in laboratory animal bone. J. Orthop. Res. 2, 97–101 (1984).

    Article  CAS  Google Scholar 

  19. Cho, T-J. et al. Differential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing. J. Bone Miner. Res. 17, 513–520 (2002).

    Article  CAS  Google Scholar 

  20. Murnaghan, M. et al. Time for treating bone fracture using rhBMP-2: a randomized placebo controlled mouse fracture trial. J. Orthop. Res. 23, 625–631 (2005).

    Article  CAS  Google Scholar 

  21. Sipe, J.B. et al. Localization of bone morphogenetic proteins (BMPs)-2,-4, and-6 within megakaryocytes and platelets. Bone 35, 1316–1322 (2004).

    Article  CAS  Google Scholar 

  22. McLeod, M.J. Differential staining of cartilage and bone in whole mouse fetuses by alcian blue and alizarin red S. Teratology 22, 299–301 (1980).

    Article  CAS  Google Scholar 

  23. Brent, A.E. et al. A somatic compartment of tendon progenitors. Cell 113, 235–248 (2003).

    Article  CAS  Google Scholar 

  24. Lanske, B. et al. The parathyroid hormone (PTH)/PTH-related peptide receptor mediates actions of both ligands in murine bone. Endocrinology 139, 5194–5204 (1998).

    Article  CAS  Google Scholar 

  25. Bernard, M.P. et al. Nucleotide sequences of complementary deoxyribonucleic acids for the pro alpha 1 chain of human type I procollagen. Statistical evaluation of structures that are conserved during evolution. Biochemistry 22, 5213–5223 (1983).

    Article  CAS  Google Scholar 

  26. Kohno, K. et al. Isolation and characterization of a cDNA clone for the amino-terminal portion of the pro-alpha 1(II) chain of cartilage collagen. J. Biol. Chem. 259, 13668–13673 (1984).

    CAS  PubMed  Google Scholar 

  27. Razzaque, M.S. et al. Conditional deletion of Indian hedgehog from collagen type 2alpha1-expressing cells results in abnormal endochondral bone formation. J. Pathol. 207, 453–461 (2005).

    Article  CAS  Google Scholar 

  28. Desbois, C. et al. The mouse osteocalcin gene cluster contains three genes with two separate spatial and temporal patterns of expression. J. Biol. Chem. 269, 1183–1190 (1994).

    CAS  PubMed  Google Scholar 

  29. Oldberg, A. et al. Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc. Natl. Acad. Sci. USA 83, 8819–8823 (1986).

    Article  CAS  Google Scholar 

  30. Niikura, T. et al. Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures. J. Orthop. Res. 24, 1463–1471 (2006).

    Article  CAS  Google Scholar 

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We thank A. Radin for fabricating the mouse fracture device and B. Donoff and L. Gamer for reviewing the manuscript. Mice carrying a floxed Bmp2 allele (Bmp2c/c) were provided to V.R. by Wyeth Research through a Material Transfer Agreement with Harvard University.

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Authors and Affiliations



This study was designed by V.R. and C.J.T. Phenotype assessment was performed by K.T., A.B., K.C. and B.D.H. S.K., L.G. and T.E. performed the initial fracture studies and contributed to analyses of the data.

Corresponding author

Correspondence to Vicki Rosen.

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Competing interests

T.E. is a consultant for, and receives grant support from, Stryker Biotech.

Supplementary information

Supplementary Fig. 1

Hindlimbs of mice lacking BMP2 have spontaneous fractures that do not heal. (PDF 1047 kb)

Supplementary Fig. 2

Levels of Bmp5 and Bmp6 in fracture calluses. (PDF 725 kb)

Supplementary Fig. 3

Skin wounds are not affected by removal of Bmp2 by Prx1::cre. (PDF 3118 kb)

Supplementary Table 1

Primer sequences. (PDF 45 kb)

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Tsuji, K., Bandyopadhyay, A., Harfe, B. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 38, 1424–1429 (2006).

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