PGC1β对类风湿关节炎破骨细胞PPARγ通路激活的关键调控作用研究

弄清破骨细胞（Oc）形成及活化调控机制是阻断类风湿关节炎（RA）骨破坏、降低致残的关键。我们前一个国家自然已证实PPARγ通路激活可抑制RA-Oc形成及活化，临床研究PPARγ激动剂治疗RA有效但不理想，提示可能存在其他重要调控因素。新近发现生理状态下Oc的PPARγ通路激活需共激活分子PGC1β的参与。我们前期研究发现RA患者Oc前体PGC1β表达降低，提示PGC1β可能在RA-Oc的PPARγ通路激活过程中起关键调控作用。本课题拟分别从体外（慢病毒PGC1β-RNAi转染RA-Oc前体细胞）和体内（造血细胞系特异性条件敲除PGC1β小鼠）探讨缺乏PGC1β能否阻碍PPARγ激动剂对RA-Oc形成、活化及CIA小鼠关节骨破坏的抑制作用；再用荧光素酶报告基因技术和ChIP明确PGC1β转录调控的信号通路，旨在明确PGC1β能否成为阻断RA骨破坏的新靶点并为开发调控PGC1β药物提供依据。

The mechanisms of osteoclast (Oc) differentiation and activation is critical for preventing joint destruction and reducing disability in rheumatoid arthritis (RA). Our results of previous National Natural Science Foundation of China has proved that the activation of PPARγ pathway can inhibit RA-Oc differentiation and activation. However, clinical studies showed that PPARγ agonist therapy for patients with active RA was effective but not ideal, suggesting that there may be other important regulatory factors for PPARγ pathway activation in RA. Recent research found that the activation of PPARγ pathway in osteoclasts depended on PPARγ coactivator 1β (PGC1β) under physiological condition. We found that PGC1β mRNA expression in peripheral blood monocytes (PBMs, regarded as pre-Oc) from RA patients was significantly lower than in those from healthy controls, indicating that PGC1β may play a key regulatory role in PPARγ pathway activation of RA-Oc. To investigate whether the lack of PGC1β could hinder PPARγ agonist from inhibiting RA-Oc differentiation and activation and joint destruction in collagen-induced arthritis (CIA) mice, we will set up Lentiviral- PGC1β-RNAi to transfect PBMs in vitro and generated conditional PGC1β knock-out CIA mice which were deleted PGC1β in hematopoietic lineages. Furtherly, we will apply the luciferase reporter gene technology and chromatin immunoprecipitation assay to identify PGC1β transcriptional signaling pathways in RA-Oc. The aim of this study was to further elucidate the mechanism of osteoclast differentiation, activation and joint destruction in RA, to determine whether PGC1β be a new target preventing RA joint destruction and provide experimental evidence for exploring new drug regulating PGC1β.