骨丢失是抗瓜氨酸蛋白抗体（ACPA）阳性类风湿关节炎（RA）的治疗难点。最新研究显示ACPA依赖PAD4及自分泌IL-8/CXCR1/2环路诱导破骨细胞活化并介导骨丢失，为难治性RA的治疗提供新契机。雷公藤临床治疗RA疗效确切，其主要活性成分雷公藤甲素能较好阻止RA小鼠关节骨破坏，降低RA患者和小鼠抗CCP、抗MCV抗体和巨噬细胞分泌IL-8水平等，但对难治性RA骨丢失的作用和机制不清楚。本项目通过瓜氨酸化II型胶原诱导关节炎和ACPA诱导骨丢失小鼠模型及体外ACPA诱导破骨细胞分化模型，研究雷公藤甲素对难治性RA骨丢失的作用，观察破骨细胞活化功能，并从PAD4及IL-8/CXCR1/2入手探索其作用途径，最后采用PAD4-/-小鼠和RNA干扰技术确证分子靶点。相关研究结果将为指导雷公藤的临床合理用药提供科学依据。

Periarticular and systematic bone loss is the key and difficulty in the treatment of more erosive and aggressive rheumatoid arthritis (RA). The latest international research shows that anti citrullinated protein antibody (ACPA) induced osteoclast differentiation and bone loss, which plays an important role in RA. Triptolide can reduce the content of anti-CCP in sera of RA patients and prevent bone destruction of RA in mice, but the exact action triptolide on ACPA-positive RA is still unclear. In this project, citrullinated collagen II induced arthritis in mice，ACPA induced bone loss in mice and ACPA-induced osteoclast differentiation from raw264.7 cells were used. The effect of triptolide on the bone loss of these model mice were investigated by clinical score, microCT and the levels of CTX-1 and TRAP5b+ in sera. The effect of triptolide on osteoclast differentiation induced by ACPA, and the expressions of IL-8, CXCR1/2, PADI4 in joints of bone loss of mice and in osteoclast induced by ACPA were also observed by IP, WB or qPCR. PADI4 deficiency mice were used. The expected results will clear the inhibitory effect of triptolide on bone loss of ACPA-positive RA and the mechanism is related to the regulation of IL-8/CXCR1/2 signal pathway. This will provide scientific experimental basis for clinical rational drug use.