Abstract
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 in vitro 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 (p < 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 in vitro 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 (p < 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 (p < 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.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial inflammation, pannus hyperplasia, and cartilage destruction in joints (McInnes and Schett, 2011)
hematoxylin and eosin (H&E) staining showed that, compared with the collagen-induced arthritis (CIA) group, PFD significantly alleviated synovial hyperplasia and inflammatory cell infiltration in the knee joints (p < 0.05) (Figures 1D,F); immunohistochemistry indicated that PFD effectively reduced VEGF protein expression in CIA joints (Figure 1E)
The expression of MMP-3 in the synovium and cartilage tissues of CIA rats was significantly higher than that in control rats, but was significantly lower in the groups treated with PFD and MTX than in CIA rats (Figures 2A–E)
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial inflammation, pannus hyperplasia, and cartilage destruction in joints (McInnes and Schett, 2011). Current disease-modifying anti-rheumatic drugs and biological agents used to alleviate the clinical symptoms of RA have obvious adverse effects and are expensive (Guo et al, 2018b). Pirfenidone (PFD) could effectively inhibit fibroblast proliferation, alleviate local inflammatory cell infiltration, and reduce collagen deposition in vivo (Nakazato et al, 2002; Kakugawa et al, 2004). It could regulate wound healing and inhibit endothelial cell angiogenesis in vitro (Liu et al, 2017). The pathological and regulatory mechanisms underlying the antiRA effects of PFD have not been investigated so far
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