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

Abstract

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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Acknowledgements

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

Authors

Contributions

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). https://doi.org/10.1038/ng1916

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  • DOI: https://doi.org/10.1038/ng1916

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