| First Author | Wu M | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 38 | Pages | 10119-10124 |
| PubMed ID | 28864530 | Mgi Jnum | J:253635 |
| Mgi Id | MGI:6094942 | Doi | 10.1073/pnas.1619294114 |
| Citation | Wu M, et al. (2017) Cbfbeta governs osteoblast-adipocyte lineage commitment through enhancing beta-catenin signaling and suppressing adipogenesis gene expression. Proc Natl Acad Sci U S A 114(38):10119-10124 |
| abstractText | The mechanism underlying how transcription factors regulate mesenchymal stem cell lineage commitment remains unclear. To determine the role of core-binding factor subunit beta (Cbfbeta) in osteoblast lineage commitment, we generated three mouse models by deleting Cbfbeta at different osteoblast lineage stages. We demonstrated that the Cbfbeta(f/f)Prx1-Cre, Cbfbeta(f/f)Col2alpha1-Cre, and Cbfbeta(f/f)Osx-Cre mice exhibited severe osteoporosis with substantial accumulation of marrow adipocytes resembling aged bone from enhanced adipogenesis, indicating that mesenchymal stem cells and osteoblasts can be programed and reprogramed, respectively, into adipocytes. Consistently, Cbfbeta-deficient calvarial cells and bone marrow mesenchymal stem cells displayed strong adipogenic potential, with 5- to approximately 70-fold increased adipocyte gene expression, which can be rescued by Cbfbeta overexpression. Canonical Wnt signaling was impeded in the Cbfbeta-deficient cells, with approximately 80% decrease of Wnt10b expression. Accordingly, ChIP and luciferase assays demonstrated that Cbfbeta/RUNX2 binds to Wnt10b promoter driving Wnt10b expression. Furthermore, Wnt3a suppressed adipogenesis but did not rescue osteoblastogenesis in Cbfbeta-deficient cells. Notably, mixing culture of Cbfbeta-deficient with normal cells demonstrates that Cbfbeta functions not only through WNT paracrine pathway but also through endogenous signaling. Further analysis shows that Cbfbeta/RUNX2 inhibits c/ebpalpha expression at transcriptional level. Our results show that, besides its osteogenic role, Cbfbeta governs osteoblast-adipocyte lineage commitment both cell nonautonomously through enhancing beta-catenin signaling and cell autonomously through suppressing adipogenesis gene expression to maintain osteoblast lineage commitment, indicating Cbfbeta may be a therapeutic target for osteoporosis. |
