Gan Donghao, Cheng Wenxiang, Ke Liqing, Sun Antonia RuJia, Jia Qingyun, Chen Jianhai, Lin Jietao, Li Jian, Xu Zhanwang, Zhang Peng
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Pharmacol. 2021 Mar 5;12:631891. doi: 10.3389/fphar.2021.631891. eCollection 2021.
Clinical studies have shown that pirfenidone (PFD) effectively relieves joint pain in rheumatoid arthritis (RA) patients. However, the detailed mechanisms underlying the anti-RA effects of PFD have not been investigated. This study was undertaken to investigate the repurposing of PFD for the treatment of RA, and explore its anti-rheumatic mechanisms. A collagen-induced arthritis (CIA) rat model was used to observe joint pathological changes following PFD treatment. Based on bioinformatics to predict the mechanism of PFD anti-RA, using EA. hy926 and TNF-α-induced MH7A cells to establish model to explore its biological mechanism from the perspectives of synovial inflammation and angiogenesis. PFD significantly relieved pathological changes, including joint swelling, synovial hyperplasia, inflammatory cell infiltration and joint destruction. PFD was also associated with reduced expression of MMP-3 and VEGF in articular chondrocytes and synovial cells of CIA rats ( < 0.05). Using bioinformatic methods, we predicted that PFD inhibits cell inflammation and migration by interfering with the JAK2/STAT3 and Akt pathways. These results were verified using models. In particular, PFD effectively reduced the expression of pro-inflammatory, chondrogenic, and angiogenic cytokines, such as IL-1β, IL-6, IL-8, MMP-1/3/2/9 and VEGF ( < 0.05), in TNF-α-induced MH7A cells. In addition, PFD significantly reduced the production of MMP-2/9 and VEGF in EA. hy926 cells, thereby weakening migration and inhibiting angiogenesis ( < 0.05). These findings suggest that PFD may alleviate the pathological process in CIA rats, by inhibiting inflammation and angiogenesis through multiple pathways, and serve as a potential therapeutic drug for RA.
临床研究表明，吡非尼酮（PFD）可有效缓解类风湿关节炎（RA）患者的关节疼痛。然而，PFD抗RA作用的详细机制尚未得到研究。本研究旨在探讨PFD用于治疗RA的新用途，并探索其抗风湿机制。采用胶原诱导性关节炎（CIA）大鼠模型观察PFD治疗后的关节病理变化。基于生物信息学预测PFD抗RA的机制，利用EA.hy926和TNF-α诱导的MH7A细胞建立模型，从滑膜炎症和血管生成的角度探索其生物学机制。PFD显著减轻了病理变化，包括关节肿胀、滑膜增生、炎性细胞浸润和关节破坏。PFD还与CIA大鼠关节软骨细胞和滑膜细胞中MMP-3和VEGF表达降低有关（<0.05）。使用生物信息学方法，我们预测PFD通过干扰JAK2/STAT3和Akt途径抑制细胞炎症和迁移。这些结果在模型中得到了验证。特别是，PFD有效降低了TNF-α诱导的MH7A细胞中促炎、软骨生成和血管生成细胞因子的表达，如IL-1β、IL-6、IL-8、MMP-1/3/2/9和VEGF（<0.05）。此外PFD显著降低了EA.hy926细胞中MMP-2/9和VEGF的产生，从而减弱迁移并抑制血管生成（<0.05）。这些发现表明，PFD可能通过多种途径抑制炎症和血管生成来减轻CIA大鼠的病理过程，并可作为RA的潜在治疗药物。
