Meprin介导的骨细胞活性氧生成在老年性骨质疏松中的作用及机制研究

Age-related osteoporosis(OS) is common disease in clinic and aggravated the life quality of elderly people. Patients with age-related OS have decreased bone mineral density(BMD)and increased bone fragility at the same time, result in higher risk of fragilitic fracture.The pathogenesis of age-related OS is not entirely knew up to now.Reseachers paid more attention to the relationship between osteocyte and age-related OS in recent years.The recent study found that increased reactive oxygen species(ROS) could induce osteocyte apoptosis and down-regulated expression of Connexin 43(Cx43) in osteocyte,and then promote the development of age-related OS.However,the mechanism of ROS produce in osteocyte is not clear. Our preceding study found that metalloproteases Meprin could activate epidermal growth factor receptor(EGFR) and induce ROS produce in macrophages。Other researches found that Meprin and EGFR are both expressed on the surface of osteocyte cell membrane.On the other hand,estradiol and testosterone could inhibit expression and activity of Meprin in vivo.We suppose that with the blood level of sex hormone decrease gradually in vivo,the expression and activity of Meprin on osteocyte maybe increase gradually.Meprin activate EGFR through activate EGFR ligand and induce ROS produce in osteocyte,which involve in development of age-related OS.In our study. we want to use lentivirus which contain Merin-RNA and Meprin si-RNA to transfect animal and cell to regulate the expression of Meprin to learn the association and mechanism of ROS produce induced by Meprin in osteocyte and age-related OS.Our study should help us to understand the pathogenesis of age-related OS further.

老年性骨质疏松以骨密度下降和骨脆性增加为特点，年龄相关的氧化应激增强与骨质疏松的关系目前受到很大的重视。研究发现氧化应激产生的细胞内活性氧（ROS）可导致骨细胞凋亡和细胞间缝隙连接蛋白Cx43表达减少，而上述改变与老年性骨质疏松相关。Meprin在体内有促进氧化应激的作用，相关研究和我们的前期工作发现Meprin具有活化表皮生长因子受体（EGFR）配体进而激活EGFR的作用，可介导巨噬细胞内ROS生成，但Meprin对骨细胞的作用目前未见相关报道。研究发现骨细胞内ROS生成与EGFR的下游信号通路rac-STAT途径有关，上游调控机制不清楚。我们推测:1.Meprin通过激活骨细胞表面EGFR及其下游rac-STAT途径介导ROS生成；2.Meprin通过诱导骨细胞内ROS生成，导致骨细胞凋亡和Cx43表达减少，参与老年性骨质疏松的形成。