Institute of Genetics, Life Science College, Zhejiang University, Hangzhou 310058, People's Republic of China.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294.
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10119-10124. doi: 10.1073/pnas.1619294114. Epub 2017 Sep 1.
The mechanism underlying how transcription factors regulate mesenchymal stem cell lineage commitment remains unclear. To determine the role of core-binding factor subunit beta (Cbfβ) in osteoblast lineage commitment, we generated three mouse models by deleting at different osteoblast lineage stages. We demonstrated that the , and 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, -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 Cbfβ overexpression. Canonical Wnt signaling was impeded in the -deficient cells, with ∼80% decrease of Wnt10b expression. Accordingly, ChIP and luciferase assays demonstrated that Cbfβ/RUNX2 binds to promoter driving expression. Furthermore, Wnt3a suppressed adipogenesis but did not rescue osteoblastogenesis in -deficient cells. Notably, mixing culture of -deficient with normal cells demonstrates that Cbfβ functions not only through WNT paracrine pathway but also through endogenous signaling. Further analysis shows that Cbfβ/RUNX2 inhibits expression at transcriptional level. Our results show that, besides its osteogenic role, Cbfβ governs osteoblast-adipocyte lineage commitment both cell nonautonomously through enhancing β-catenin signaling and cell autonomously through suppressing adipogenesis gene expression to maintain osteoblast lineage commitment, indicating Cbfβ may be a therapeutic target for osteoporosis.
转录因子调控间充质干细胞谱系分化的机制尚不清楚。为了确定核心结合因子亚基β（Cbfβ）在成骨细胞谱系分化中的作用，我们在不同的成骨细胞谱系阶段通过删除 生成了三种小鼠模型。我们证明 、 和 小鼠表现出严重的骨质疏松症，骨髓脂肪细胞大量堆积，类似于增强脂肪生成的老年骨，表明间充质干细胞和成骨细胞分别可以被编程和重新编程为脂肪细胞。一致地，-缺陷的颅盖细胞和骨髓间充质干细胞显示出强烈的成脂潜能，脂肪细胞基因表达增加 5 至 ∼70 倍，这可以通过 Cbfβ过表达来挽救。-缺陷细胞中的经典 Wnt 信号受到阻碍，Wnt10b 的表达减少了 ∼80%。相应地，ChIP 和荧光素酶测定表明 Cbfβ/RUNX2 结合到 启动子上，驱动 表达。此外，Wnt3a 抑制脂肪生成，但不能挽救 -缺陷细胞中的成骨作用。值得注意的是，-缺陷细胞与正常细胞混合培养表明 Cbfβ 不仅通过 WNT 旁分泌途径，而且通过内源性信号发挥作用。进一步分析表明，Cbfβ/RUNX2 在转录水平上抑制 表达。我们的结果表明，除了其成骨作用外，Cbfβ 还通过增强 β-连环蛋白信号非自主地和通过抑制成脂基因表达自主地调节成骨细胞-脂肪细胞谱系分化，以维持成骨细胞谱系分化，表明 Cbfβ 可能是骨质疏松症的治疗靶点。
