mTOR信号途径在肥胖相关骨质疏松小鼠BMSCs定向分化及表型转换中的机制研究

Obesity-related osteoporosis is characterized by increased adipose and bone metabolism disorder because of energy accumulation. The imbalance between osteoblasts and adipocytes all derived from bone marrow mesenchymal stem cells(BMSCs) is an important cause of Obesity-related osteoporosis. However, the mechanism of directional differentiation and phenotypic switch of BMSCs to osteoblasts and adipocytes is still unknown. Our research found that mTOR can sense the extracellular energy status to stimulate the adipogenesis of C3H10T1/2.We also discovery there is the mTOR signaling pathway in the BMSCs of C57BL/6 mice. Our research object to investigate the effect of excess energy on the directional differentiation and phenotypic switch of BMSCs and the role of mTOR singanling pathway in the directional differentiation and phenotypic switch of BMSCs, to discover the mechanism of the occurrence of obesity-related osteoporosis. This study will facilitate the understanding of the inhibition of adipogenesis of BMSCs and the phenotypic switch from adipocytes to osteoblasts, provide an important basis for research and development of therapy through this signaling pathway for diseases with increased energy accumulation as obesity-related osteoporosis.

肥胖相关的骨质疏松是一个能量堆积而引起脂肪组织过剩及骨代谢紊乱的过程，共同起源于骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)的脂肪细胞与骨细胞之间的动态平衡失调是其发生的重要原因。而对BMSCs成脂成骨分化能力及两者表型转化在骨质疏松发病中的作用及具体信号机制尚不清楚。申请者的前期工作发现mTOR可能通过感受细胞外能量状态的变化，从而促进干细胞系C3H10T1/2细胞向脂肪细胞定向分化的过程；在分离培养的C57BL/6小鼠BMSCs中，也存在mTOR信号通路。本课题拟通过研究机体能量过剩状态对BMSCs定向分化能力及表型转化的调控及mTOR在BMSCs定向分化能力及表型转化中的作用，揭示肥胖相关骨质疏松发生的分子机制，为今后开发抑制BMSCs向脂肪细胞定向分化、促进脂肪细胞向骨细胞表型转化、防治骨质疏松的药物提供理论与实验基础。

肥胖相关的骨质疏松是一个能量堆积而引起脂肪组织过剩及骨代谢紊乱的过程。大量研究已经证明肥胖与骨代谢是相互关联的。成骨细胞（骨形成细胞）和脂肪细胞（能量储存细胞）都起源于骨髓间充质干细胞，两者可以相互转换，并且存在“此消彼长”的关系。我们的研究发现小鼠BMSCs成脂及成骨分化过程中存在mTOR信号通路的表达，并且能量状态的改变可以影响小鼠BMSCs的成脂成骨分化及mTOR信号通路；在体水平上，高能量状态促进去势骨质疏松小鼠BMSCs的成脂分化而抑制其成骨分化。mTOR-ERK1/2信号通路调节了BMSCs向脂肪细胞定向分化能力及表型转换。这些研究结果为肥胖相关性骨质疏松的治疗提供重要的理论基础和潜在的新靶标。