Cbfß governs osteoblast-adipocyte lineage commitment through enhancing ß-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 (Cbfß) in osteoblast lineage commitment, we generated three mouse models by deleting Cbfß at different osteoblast lineage stages. We demonstrated that the Cbfßf/fPrx1-Cre, Cbfßf/fCol2α1-Cre, and Cbfßf/fOsx-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, Cbfß-deficient calvarial cells and bone marrow mesenchymal stem cells displayed strong adipogenic potential, with 5- to ∼70-fold increased adipocyte gene expression, which can be rescued by Cbfß overexpression. Canonical Wnt signaling was impeded in the Cbfß-deficient cells, with ∼80% decrease of Wnt10b expression. Accordingly, ChIP and luciferase assays demonstrated that Cbfß/RUNX2 binds to Wnt10b promoter driving Wnt10b expression. Furthermore, Wnt3a suppressed adipogenesis but did not rescue osteoblastogenesis in Cbfß-deficient cells. Notably, mixing culture of Cbfß-deficient with normal cells demonstrates that Cbfß functions not only through WNT paracrine pathway but also through endogenous signaling. Further analysis shows that Cbfß/RUNX2 inhibits c/ebpα expression at transcriptional level. Our results show that, besides its osteogenic role, Cbfß governs osteoblast-adipocyte lineage commitment both cell nonautonomously through enhancing ß-catenin signaling and cell autonomously through suppressing adipogenesis gene expression to maintain osteoblast lineage commitment, indicating Cbfß may be a therapeutic target for osteoporosis.