GDF11- Tmem18调节BMSCs向成骨/成脂细胞分化与Wnt信号通路的关系研究

Bone marrow mesenchymal stem cells (BMSCs) induce osteogenesis and inhibit the adipogenic differentiation, which is the key to prevention and treatment of osteoporosis. The Wnt signaling pathway plays an important role on bone formation. In previous studies, we found that growth differentiation factor 11 (GDF11) promote BMSCs osteogenic differentiation. Transmembrane protein 18 (Tmem18) expression level is significantly decreased in BMSCs osteogenic differentiation. The overexpression of Tmem18 promotes BMSCs cell differentiation into fat, but the correlation of Tmem18 with osteoblast differentiation is unclear. In this project we will investigate how Tmem18 inhibits differentiation of BMSCs into osteoblasts and negatively regulates Wnt signal. Based on the findings, we will screen key signaling molecules in downstream of osteogenic differentiation regulated by Tmem18. Then we will identify underlying mechanism that Tmem18 regulates Wnt signaling pathway and BMSCs bone differentiation. In addition, we will evaluate the therapeutic effect of Tmem18 on osteoporosis at the animal level. By revealing the biological significance of Tmem18 on BMSCs osteogenic differentiation we will provide new ideas and clues for the prevention and treatment of osteoporosis by using BMSCs.

骨髓间充质干细胞（BMSCs）诱导成骨而抑制成脂细胞分化是骨质疏松症防治的关键，Wnt信号通路对骨形成起着重要作用。我们的研究发现，生长分化因子11（GDF11）促进BMSCs 成骨细胞分化，跨膜蛋白18（Tmem18）表达却显著下降；而Tmem18高表达促进BMSCs成脂细胞分化， 但Tmem18与成骨细胞分化是否相关尚不清楚。本项目在证实Tmem18 抑制BMSCs 向成骨细胞分化，同时负向调控Wnt信号的基础上，进一步筛选Tmem18调控BMSCs成骨分化下游可能的关键信号分子，初步阐明Tmem18蛋白通过Wnt信号通路调控BMSCs成骨分化的分子机制。另外，动物水平鉴定Tmem18对骨质疏松症的治疗作用。初步揭示Tmem18表达与BMSCs成骨分化的生物学意义，为BMSCs用于骨质疏松症的防治提供新思路和深入研究线索。

骨髓间充质干细胞（BMSCs）诱导成骨而抑制成脂细胞分化是骨质疏松症防治的关键。本项目围绕跨膜蛋白18（Tmem18）依赖骨形成的Wnt/β-catenin 关键信号通路调控BMSCs成骨分化的核心问题进行研究。我们取得的主要研究成果为：（1）Tmem18在大鼠BMSCs成骨分化过程中表达下调，并通过负向调控β-catenin进而抑制BMSCs向成骨细胞分化；（2）miR-664a-5p靶向HMGA2促进人BMSCs向成骨细胞分化；（3）miR-452-3p 通过靶向 Smad4 抑制成骨细胞分化。本研究丰富了我们对BMSCs成骨分化的分子机制的理解，并为BMSCs 临床应用促进骨修复和骨质疏松症治疗提供继续深入研究的线索。