EZH2抑制BMP2在骨质疏松BMSCs向成骨细胞分化中的分子机制

The inhibited osteogenic differentiation of bone marrow-derived mesenchymal stem cells（BMSCs） and decreased number of osteoblast are reasons for osteoporosis. EZH2 appears to be an important orchestrator of skeletal development, postnatal bone remodelling and BMSCs fate determination in vitro and in vivo. Further studies will be needed to address this mechanism of EZH2 inhibiting osteoporotic BMSCs osteogenic differentiation. In early research, we used the EZH2 inhibitor in ovariectomy mice osteoporosis model, and found the bone mineral density of the model increasing significantly compared to the control groups. We used the radiation-induced rat osteoporotic BMSCs, and found the osteogenic differentiation decreased and BMP2 declined obviously，however, the expression of EZH2 in BMSCs increased obviously,. Based on these early findings, we try to find whether the EZH2 inhibitor in ovariectomy mice osteoporosis model could be used for the treatment of the osteoporosis, and explore the molecular mechanism of the EZH2 inhibiting BMP2 signal pathway of the osteoporotic BMSCs osteogenic differentiation. We hope this study could provide a new target for the medical treatment of osteoporosis.

骨髓间充质干细胞（BMSCs）向成骨细胞方向分化受抑，致骨形成细胞数减少是骨质疏松症的原因之一。EZH2在管控骨骼发育、骨改建和BMSCs分化方向中发挥重要作用，然而其调控骨质疏松BMSCs向成骨细胞分化的分子机制的研究有待进一步深入。申请者在前期研究中发现，在双侧卵巢切除骨质疏松小鼠体内应用小分子抑制剂，抑制EZH2作用后，可明显改善骨质疏松小鼠骨量；辐照大鼠骨质疏松BMSCs向成骨细胞分化能力下降，伴随着EZH2表达水平升高和BMP2表达水平下降。本课题拟以双侧卵巢切除小鼠骨质疏松模型和与之相对应的BMSCs为研究对象，侧重于了解抑制EZH2状态下，骨质疏松的治疗作用，分析EZH2与BMP2表达水平的相互变化，深入探讨EZH2抑制BMP2通路在骨质疏松BMSCs向成骨细胞分化的分子机制。有助于加深或更新骨质疏松BMSCs向成骨细胞分化的认识，有望提出促进骨质疏松骨形成的新举措。

骨髓间充质干细胞(BMSCs)向成骨细胞方向分化受抑，致骨形成细胞数减少是骨质疏松 症的原因之一。EZH2在管控骨骼发育、骨改建和BMSCs分化方向中发挥重要作用，然而其调控 骨质疏松BMSCs向成骨细胞分化的分子机制的研究有待进一步深入。申请者在前期研究中发现 ，在双侧卵巢切除骨质疏松小鼠体内应用小分子抑制剂，抑制EZH2作用后，可明显改善骨质疏 松小鼠骨量;辐照大鼠骨质疏松BMSCs向成骨细胞分化能力下降，伴随着EZH2表达水平升高和B MP2表达水平下降。本课题发现：1、雌激素处理后，骨髓间充质干细胞EZH2表达减少。2、雌激素抑制了骨髓间充质干细胞Smad的磷酸化。3、雌激素抑制了骨髓间充质干细胞H3K27的表达。4、雌激素抑制了骨髓间充质干细胞Ki67的表达，促进p16和p53表达。 结论:小鼠卵巢摘除后体内的BMSC内EZH2表达增加，促进了细胞的衰老，这种作用可被雌激素抑制。有助于加深或更 新骨质疏松BMSCs向成骨细胞分化的认识，有望提出促进骨质疏松骨形成的新举措。