基于RANKL/caspase-1信号介导的PINK1剪切调控线粒体自噬功能在破骨细胞分化及骨质疏松症中的作用及机制研究

伴随人口老龄化进程，我国骨质疏松症的患病人数逐年增长，造成了沉重的社会和经济负担。线粒体ROS增多导致破骨细胞骨吸收增强是骨质疏松发生的重要原因，而线粒体自噬作为线粒体ROS的重要调控机制，其在破骨细胞中的作用尚没有明确报道。申请人通过前期研究发现，PINK1通过RANKL/caspase-1信号被剪切降解，导致线粒体自噬抑制，线粒体ROS升高，促进破骨细胞分化；而破骨细胞特异性PINK1基因敲除的小鼠表现出骨量下降、破骨细胞增多、骨吸收增强。本项目将通过：1）人体、动物样本检测PINK1与骨量相关性；2）基因敲除动物研究；3）体外PINK1介导线粒体自噬对破骨细胞分化作用及机制；4）PINK1为靶点治疗骨质疏松，四个方面阐明PINK1介导的线粒体自噬在破骨细胞分化和骨质疏松发生发展中的作用及机制，为骨质疏松预防和治疗提供新的理论依据。

With the aging of the population, more and more patients suffer from osteoporosis, causing a heavy social and economic burden. Increased mitochondrial ROS leads to enhanced bone resorption in osteoclasts, which is an important pathogenesis of osteoporosis. However, mitophagy, as an important regulatory mechanism of mitochondrial ROS, has not been clearly studied in osteoclastogenesis. The results of our preliminary study showed that PINK1 is cleaved by RANKL/caspase-1 pathway, leading to the inhibition of mitophagy, which in turn increases mitochondrial ROS and promotes osteoclast differentiation. Mice with osteoclast-specific PINK1 knockout exhibits decreased bone mass, increased osteoclast activity, and enhanced bone resorption. This project will perform: 1) human and animal samples detection; 2) gene knock-out animal research; 3) PINK1-mediated mitophagy on osteoclast differentiation and its mechanism; 4) the potential of osteoporosis treatment using PINK1 agonist. This project will focus on the role of PINK1-mediated mitophagy in the development of osteoporosis and osteoclast differentiation, which provides a new theoretical basis for the prevention and treatment of osteoporosis.