PGC1β通过线粒体氧化磷酸化/ROS通路调控类风湿关节炎成纤维样滑膜细胞促炎及关节侵蚀的分子机制

成纤维样滑膜细胞（FLS）促炎及关节侵蚀是造成类风湿关节炎（RA）关节炎症及破坏的重要原因，但调控机制不清。我们前期报道转录因子PGC1β促进RA-FLS促炎、迁移和侵袭且抑制凋亡。预实验表达谱芯片分析发现PGC1β主要调控线粒体氧化磷酸化（OXPHOS），且发现PGC1β促进RA-FLS活性氧（ROS）产生，激活NF-κB通路。因此我们提出RA-FLS中上调的PGC1β通过调控线粒体OXPHOS增加ROS水平激活NF-κB通路从而促进RA-FLS促炎及关节侵蚀的假说。本项目拟通过临床横断面及前瞻性研究、RA-FLS体外实验基因调控PGC1β、药物干预ROS水平及动物实验CIA小鼠关节腔注射慢病毒shRNA抑制PGC1β，明确PGC1β是否通过线粒体OXPHOS/ROS激活NF-κB通路促进RA-FLS促炎及关节侵蚀及阻断PGC1β能否抑制RA关节炎症及破坏，为开发RA治疗药提供新靶点。

Fibroblast-like synoviocytes (FLS) are critical for joint destruction of rheumatoid arthritis (RA) through mediating inflammation, cartilage degradation and bone erosion. However, little was known about related regulating mechanism. We previously reported that peroxisome proliferator-activated receptor gamma coactivator (PGC)1β, a transcription factor, promoted pro-inflammatory effect, migration, invasion of RA-FLS and inhibited their apoptosis. Preliminary experiments of microarray analysis and KEGG pathway analysis on lentiviral shRNA-PGC1β transfected RA-FLS identified mitochondrial oxidative phosphorylation (OXPHOS) as the most differentially regulated gene set of PGC1β. We also found that PGC1β can increase the production of reactive oxygen (ROS) and activate NF-κB pathway in RA-FLS. Therefore, our hypothesis is that elevated PGC1β in RA-FLS will promote mitochondrial OXPHOS and increase ROS level, leading to pro-inflammatory effect and joint destruction by activating NF-κB pathway. In this project, we plan to perform cross-sectional and prospective clinical studies, up or down regulating PGC1β in RA-FLS for mitochondrial OXPHOS/ROS analysis, drug intervention of ROS level for NF-κB phosphorylation and RA-FLS functional experiments, and intra-articular injection of lentiviral shRNA suppressing PGC1β in CIA mice for treatment. We aim to determine whether PGC1β promotes RA-FLS pro-inflammatory effect and joint destruction by regulating mitochondrial OXPHOS and increasing ROS to activate NF-κB pathway, and whether blockage of PGC1β can inhibit joint inflammation and destruction in RA, in order to develop a new therapeutic target for RA.