Cbfβ governs osteoblast-adipocyte lineage commitment through enhancing β-catenin signaling and suppressing adipogenesis gene expression

The mechanism underlying how transcription factors regulate mesenchymal stem cell lineage commitment remains unclear. To determine the role of core-binding factor subunit beta (Cbf beta) in osteoblast lineage commitment, we generated three mouse models by deleting Cbf beta at different osteoblast lineage stages. We demonstrated that the Cbf beta(f/f)Prx1-Cre, Cbf beta(f/f)Col2 alpha 1-Cre, and Cbf beta(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, Cbf beta-deficient calvarial cells and bone marrow mesenchymal stem cells displayed strong adipogenic potential, with 5- to similar to 70-fold increased adipocyte gene expression, which can be rescued by Cbf beta overexpression. Canonical Wnt signaling was impeded in the Cbf beta-deficient cells, with similar to 80% decrease of Wnt10b expression. Accordingly, ChIP and luciferase assays demonstrated that Cbf beta/RUNX2 binds to Wnt10b promoter driving Wnt10b expression. Furthermore, Wnt3a suppressed adipogenesis but did not rescue osteoblastogenesis in Cbf beta-deficient cells. Notably, mixing culture of Cbf beta-deficient with normal cells demonstrates that Cbf beta functions not only through WNT paracrine pathway but also through endogenous signaling. Further analysis shows that Cbf beta/RUNX2 inhibits c/ebp alpha expression at transcriptional level. Our results show that, besides its osteogenic role, Cbf beta 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 Cbf beta may be a therapeutic target for osteoporosis.