破骨细胞功能下降引起2型糖尿病骨折增加的分子机理研究

破骨细胞功能下降是2型糖尿病患者骨转换指标下降，骨密度正常但骨折风险增加的根本原因。我们在前期研究中，发现破骨细胞前体细胞（CD14+ PBMCs）中miR-503的表达可以抑制其向破骨细胞分化，而2型糖尿病患者CD14+ PBMCs中miR-503表达显著升高。此外，胰岛素信号通路中的关键转录因子FoxO1与miR-503启动子区域存在结合位点，且在胰岛素抵抗/高胰岛素血症时转录活性增强，可能是2型糖尿病miR-503高表达，并导致破骨细胞功能下降的原因。本课题拟深入研究miR-503在2型糖尿病患者CD14+ PBMCs中升高的原因及作用，为探索2型糖尿病骨折风险升高的发病机理开拓新思路，为骨病的防治提供新途径。

Patients with type 2 diabetes (T2DM) are at increased risk for fragility fractures with normal or higher bone mineral density (BMD) values compared to non-diabetic controls. In addition, patients with T2DM had significantly reduced serum markers of bone turnover compared to controls. Decrease of osteoclast function may be the key reason for these phenomenon. In the prior studies, we have found that miR-503 in circulating progenitors of osteoclasts—CD14+ peripheral blood mononuclear cells (PBMCs) inhibit osteoclast differentiation and the expression of miR-503 in CD14+ PBMCs were significantly increased in T2DM. Furthermore, FoxO1, which is the key transcription factor of insulin signaling pathway, has been predicted to be combined with the promoter of miR-503. FoxO1 may increase the miR-503 expression in CD14+ PBMCs and inhibit osteoclast differentiation in T2DM patients. This project is to explore the reason and role of increased miR-503 in T2DM and will provide new insights on osteoporosis therapy.