Bone morphogenetic protein-3 is a negative regulator of bone density

Abstract

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily. Many BMPs are produced in bone and show osteogenic activity, suggesting that they may be determinants of bone mass. BMP3 was originally purified from bone as osteogenin, which induces osteogenic differentiation1. Recombinant BMP3 (rhBMP3) has no biological activity, however, leaving its role in skeletal growth unclear. Here we show that BMP3 is an antagonist of osteogenic BMPs: BMP3 dorsalizes Xenopus laevis embryos, inhibits BMP2-mediated induction of Msx2 and blocks BMP2-mediated differentiation of osteoprogenitor cells into osteoblasts. These effects appear to be mediated through activin receptors. Finally, Bmp3−/− mice have twice as much trabecular bone as wild-type littermates, indicating that BMP3, the most abundant BMP in adult bone, is a negative determinant of bone density.

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Figure 1: BMP3 is not osteogenic in vitro.
Figure 2: BMP3 dorsalizes X. laevis embryos and inhibits BMP2-induced osteogenic differentiation.
Figure 3: BMP3 inhibits Msx2 induction in mesenchymal stem cells.
Figure 4: Generation of mice deficient in Bmp3 by homologous recombination in embryonic stem (ES) cells.
Figure 5: Increased bone density in Bmp3−/− mice.

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Acknowledgements

We thank E. DeRobertis for assistance with X. laevis embryo injections; W. Goodman for guidance with histomorphometric analysis; D. Israel and J. Nove for generation of Bmp3-targeted ES cells; R. Peterson for help with initial breeding experiments; R. Maxson for 2 kb Msx2-Lux; K. Arora for CA-TKV; D. Litwack for rat Bmp3 cDNA; J. Massagué for ALK-4 and ActRII expression vectors; and J. Lengyel, U. Banerjee, A. Lusis and L. Birnbaumer for comments. This work was supported by NIH grant AR44528 (K.M.L.) and the Wendy Will Case Cancer Fund (K.M.L.).

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Correspondence to Karen M. Lyons.

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Daluiski, A., Engstrand, T., Bahamonde, M. et al. Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet 27, 84–88 (2001). https://doi.org/10.1038/83810

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