BMPR-I/II-Gαi1/3通路促成骨细胞分化的作用和机制研究

Osteoporosis is a common age-related disease featured with increased morbidity and severe complications, while the pathogenesis of osteoporosis remains unclear.It is known that bone morphogenetic protein 2 (BMP2) is a protein associated with osteogenesis, and α-subunits of the G protein (Gαi1/3) plays key role as signaling molecule that mediates several cytokines. In our previously study, we have observed that knockdown or knockout of Gαi1/3 gene significantly inhibited the activation of BMP2-induced downstream signal, associated with decreased osteogenic ability and bone mass of mice. As the evidence of the correlation between Gαi1/3 with osteogenesis, we propose that Gαi1/3 protein may promote osteoblast differentiation through BMP2-BMPR-I/II signaling pathway. This proposal is aimed to explore the mechanism under which BMP2-BMPR-I/II signaling pathway promotes osteogenesis and identify the role of Gαi1/3 protein in activating BMP2-BMPR-I/II pathway. Taken together, Gαi1/3 protein may provide us a new therapeutic strategy for prevention and treatment of osteoporosis in clinic.

骨质疏松发病率逐年上升，并发症致死率高，而骨质疏松发病机制仍不明确。骨形态发生蛋白2(BMP2)具有促进成骨作用；Gαi1/3蛋白是可介导多种细胞因子信号转导的新型关键信号分子。我们预实验结果显示敲除或敲减Gαi1/3基因均抑制了BMP2诱导的下游信号活化；shRNA慢病毒敲减Gαi1/3基因后显著抑制了小鼠成骨前体细胞的成骨能力；定量分析Gαi1/3基因敲除的小鼠骨量显著丢失。由此我们提出Gαi1/3蛋白介导BMP2-BMPR-I/II信号转导促进成骨细胞分化这一科学假说。本项目从分子、细胞及组织水平探究BMP2-BMPR-I/II信号通路促进成骨的作用机制，进一步解析Gαi1/3蛋白介导BMP2-BMPR-I/II下游信号活化的分子机制，在此基础上通过调控Gαi1/3蛋白的表达水平以达到促进成骨的目的，为临床防治骨质疏松提供新的思路和治疗靶点。

骨质疏松症是全球面临的公共健康问题，随着人口老龄化发病率逐年上升，目前仍缺乏非常安全又有效的治疗药物。骨形态发生蛋白2(BMP2)具有促进成骨作用。Gαi1/3（G蛋白抑制性α亚单位1/3）是我们证实可介导多种细胞因子信号转导的新型关键信号分子。小鼠胚胎成骨细胞前体细胞（MC3T3-E1）中实验发现：敲除Gαi1/3显著抑制BMP2诱导的MC3T3-E1成骨分化。Gαi1/3基因敲除小鼠的骨发育迟缓，骨量显著降低。我们在本项目验证了Gαi1/3蛋白介导BMP2-BMPR-I/II信号转导及促进成骨作用。系统检测了骨质疏松临床标本和小鼠模型中Gαi1/3的表达，并分析与骨质疏松的相关性。运用多种分子生物学方法和基因敲除小鼠，验证Gαi1/3介导BMP2-BMPR-I/II信号转导促成骨作用及分子机制。本项目证实Gαi1/3是调节骨形成的关键信号分子。