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

Abstract

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) 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 differentiation. 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.

c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis

“…Key genes for the regulation of embryonic organogenesis (Hoxa5, Hoxa9, Foxc1 and Foxf2) and the commitment of immature cells to multiple lineages (Pparg, Cebpa, Plxnd1, Egfl7, Mgp, Plxdc2, Ebf1 and Tcf3) were expressed at higher levels in AO cells than in AX cells, suggesting that AO cells have characteristics of immature mesenchymal cells (Wang and Reed, 1993;Luo et al, 1997;Wu et al, 1999;Rosen et al, 2000;Parker et al, 2004;Torres-Vazquez et al, 2004;Miller et al, 2007;Cole et al, 2008). The profile of AX cells, on the other hand, was indicative of both cells that are committed to the osteocyte lineage (Dlx3, Sp7, Dkk1, Ostn and Bmp3) and cells that are inclined to tumorigenesis in vivo (Cd276, Ptgs2, Vegfa, Epha2, Frzb and Sfrp1) (Kim et al, 1993;Daluiski et al, 2001;Dannenberg et al, 2001;Thomas et al, 2003;Lee et al, 2004 Zang et al, 2007;Brantley-Sieders et al, 2008;Engin et al, 2008;Li et al, 2008).…”

The BMP signaling and in vivo bone formation

“…Similarly Bmp4 CKO mice (Col1-Cre mice were used) also showed defects in bone development and postnatal bone formation (Guo et al, 2004). In contrast, Bmp3 KO mice show increased bone mass, suggesting that endogenous BMP3 antagonizes BMP signaling in vivo (Daluiski et al, 2001). Bmp6-deficient mice are viable and fertile and show no overt defects in tissues known to express Bmp6 mRNA (Solloway et al, 1998).…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…Most of the BMPs are expressed in skeletal tissue, and many are detectable in osteoblasts as well (Anderson et al, 2000). While the majority are recognized for promotion of bone formation, BMP-3, for example, is a negative regulator of bone formation (Daluiski et al, 2001). Transforming growth factor-/S (TGF-/3) is a major player in bone biology, directly inducing effects in both osteoclasts and osteoblasts.…”