基于RNase L 调控破骨细胞自噬探讨雷公藤甲素抗类风湿关节炎骨破坏的作用机制

由破骨细胞介导的骨破坏是类风湿关节炎(RA)致残的关键原因，最新研究表明自噬是破骨细胞活化致骨吸收的关键枢纽，且可被核糖核酸酶L(RNase L)激活。我们在前期已证明雷公藤甲素(TP)能降低RNase L表达和功能、延缓RA骨破坏的基础上，进一步发现此作用与抑制破骨细胞自噬有关。故此，提出“TP通过抑制RNase L介导的自噬阻止破骨细胞活化，进而延缓RA骨破坏”的假说。本项目拟采用胶原诱导型关节炎（CIA）小鼠以及体外破骨细胞分化模型，以自噬为切入点，分别从整体、细胞和分子水平明确RNase L与破骨细胞自噬的关系；通过基因敲除/基因沉默和过表达的对比研究，阐明TP通过抑制RNase L介导的自噬阻止破骨细胞活化、进而延缓RA骨破坏的机制。本项目结果将有助于阐释RA骨破坏的病理机制及TP抗RA分子机理，为基于破骨细胞的抗RA治疗提供新靶标，并为雷公藤类药物的临床合理应用提供实验依据。

Osteoclast-mediated bone destruction is the main cause of rheumatoid arthritis (RA)-induced disability. It’s reported that autophagy plays a vital role in osteoclast-induced bone resorption, which can be activated by RNase L. Interestingly, we have found that Triptolide (TP) could downregulate the RNase L expression and thus suppressed bone destruction in RA. We further found that the effect of TP on bone destruction was related to the autophagy inhibition in osteoclast. Therefore, we hypothesize that TP could inhibit osteoclast activation and bone destruction in RA by blocking the RNase L-mediated autophagy. In the present study, we aim to investigate the relationship between RNase L and osteoclast autophagy using collagen-induced arthritis (CIA) mice and osteoclast differentiation model in vitro. We will further clarify the mechanism of TP in osteoclast inactivation and bone mitigation in RA through inhibition of RNase L-mediated autophagy using gene knockout/silencing or overexpression technologies. Our results will be helpful in elucidating the pathology of bone destruction in RA and the molecular mechanism of TP in anti-RA, Also, these results will help to discovery new targets in RA therapy, and provide theoretical basis for clinical application of TP.