核糖体蛋白5（RPS5）调控破骨细胞分化减轻绝经后骨质丢失及其机制研究

Osteoporosis (OP) is characterized by reduced bone mass, bone tissue microstructure changes with increased bone fragility and decreased bone strength. The occurrence of primary osteoporosis is closely related to the excessive osteoclastogenesis in inflammatory state. Based on matrine, we synthesized a novel matrine derivative MASM with significant anti-inflammatory activity. We demonstrated that it could inhibit osteoclastogenesis and reduce the bone loss in ovariectomized mice. We found that during osteoclastogenesis, RPS5 expressions decreased significantly and MASM could maintain the RPS5 levels and reduce p-Akt levels. These results suggest that RPS5 play an important role in osteoclastogenesis, which has not been reported. Thus, the purpose of this study is to explore the roles of RPS5 in osteoclastogenesis and its molecular mechanism in vitro and in pathogenesis of primary OP in vivo to provide a new target and option for the treatment of primary osteoporosis.

骨质疏松症（Osteoporosis, OP）以骨量降低、骨组织显微结构发生改变导致骨脆性增加、骨强度下降、易骨折为特征，发病率逐年升高。绝经后骨质疏松症是常见的原发性骨质疏松症，其发生与炎症诱导的破骨细胞过度活化密切相关。课题组前期合成了有优良抗炎活性的硫代苦参碱MASM，实验显示其体外能够显著抑制破骨细胞分化，减轻去卵巢小鼠骨质丢失。核糖体蛋白5（RPS5）是MASM作用靶点之一。RAW264.7细胞诱导破骨分化时RPS5表达水平显著降低，给予MASM后RPS5水平升高，Akt磷酸化水平显著降低，提示RPS5可能通过调控Akt通路在破骨分化中发挥重要作用。本研究以MASM为突破口，通过ChIP、Co-IP等体外实验阐明RPS5调控破骨分化的分子机制，构建巨噬细胞条件敲除小鼠探讨RPS5在绝经后骨质疏松症发病中的作用，以期为原发性骨质疏松症的治疗提供新靶点、新思路和新药物。

骨质疏松症（Osteoporosis;OP）以骨量降低、骨组织显微结构发生改变导致骨脆性增加、骨强度下降、易骨折为特征，发病率逐年升高。绝经后骨质疏松症是常见的原发性骨质疏松症，其发生与炎症诱导的破骨细胞过度活化密切相关。核糖体蛋白5（RPS5）是MASM作用靶点之一。本研究明确MASM影响破骨细胞分化及其作用机制，RAW264.7细胞诱导破骨分化时RPS5表达水平显著降低，给予MASM后RPS5水平升高。构建 RPS5 shRNA和质粒慢病毒载体，研究发现MASM显著抑制Akt信号通路，且基于RPS5表达实现。当RPS5被过表达的同时使用MASM干预则显著增强MASM抑制NF-κB、MAPK和AKT通路激活的能力，提示RPS5通过调控Akt通路在破骨分化中发挥重要作用。本研究以MASM为突破口，阐明RPS5调控破骨分化的分子机制，探讨RPS5在绝经后骨质疏松症发病中的作用，为原发性骨质疏松症的治疗提供新靶点、新思路和新药物。