| First Author | Morita M | Year | 2016 |
| Journal | Sci Rep | Volume | 6 |
| Pages | 35221 | PubMed ID | 27731422 |
| Mgi Jnum | J:250177 | Mgi Id | MGI:6101601 |
| Doi | 10.1038/srep35221 | Citation | Morita M, et al. (2016) Smad4 is required to inhibit osteoclastogenesis and maintain bone mass. Sci Rep 6:35221 |
| abstractText | Bone homeostasis is maintained as a delicate balance between bone-resorption and bone-formation, which are coupled to maintain appropriate bone mass. A critical question is how bone-resorption is terminated to allow bone-formation to occur. Here, we show that TGFbetas inhibit osteoclastogenesis and maintain bone-mass through Smad4 activity in osteoclasts. We found that latent-TGFbeta1 was activated by osteoclasts to inhibit osteoclastogenesis. Osteoclast-specific Smad4 conditional knockout mice (Smad4-cKO) exhibited significantly reduced bone-mass and elevated osteoclast formation relative to controls. TGFbeta1-activation induced expression of Irf8 and Bcl6, both of which encode factors inhibiting osteoclastogenesis, by blocking their negative regulator, Prdm1, in osteoclasts in a Smad4-dependent manner. Reduced bone-mass and accelerated osteoclastogenesis seen in Smad4-cKO were abrogated by Prdm1 deletion. Administration of latent-TGFbeta1-Fc to wild-type mice antagonized LPS-induced bone destruction in a model of activated osteoclast-mediated bone destruction. Thus, latent-TGFbeta1-Fc could serve as a promising new therapeutic agent in bone diseases marked by excessive resorption. |
