School of Medicine, Huaqiao University, Quanzhou, 362021, China.
College of Chemical Engineering and Materials Sciences, Quanzhou Normal University, Quanzhou, 326000, China.
Eur J Pharmacol. 2023 Mar 15;943:175530. doi: 10.1016/j.ejphar.2023.175530. Epub 2023 Jan 20.
Cartilage degeneration and inflammation are important features of rheumatoid arthritis (RA). Chondrocyte inflammation and apoptosis have been increasingly demonstrated to be related to cartilage decomposition. In this study, we analyzed the protective role of kallistatin against RA and its associated mechanisms. We obtained in vitro and in vivo RA models using IL-1β and heat-inactivated Mycobacterium tuberculosis, respectively. Our results showed that kallistatin mitigated IL-1β-mediated chondrocyte apoptosis and inhibited the synthesis of ECM-degrading generation, like matrix metalloproteinase (MMP)-3/13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4/5, in IL-1β-mediated chondrocytes. Furthermore, kallistatin markedly suppressed IL-1β-mediated inflammation while decreasing the levels of inflammatory factors and mediators via the NF-κB pathway. Daily administration of kallistatin reduced the expression levels of PGE2, TNF-α, IL-1β, and IL-6. Histochemical analysis revealed that the kallistatin-treated rats exhibited reduced RA severity compared with control mice. In summary, kallistatin suppressed IL-1β-mediated inflammation in chondrocytes via the NF-κB pathway. Administration of kallistatin remarkably inhibited RA development, accompanied by reduced inflammation and apoptosis. Therefore, kallistatin administration can be used as a candidate therapeutic strategy for RA.
软骨退变和炎症是类风湿关节炎（RA）的重要特征。越来越多的证据表明软骨细胞炎症和凋亡与软骨分解有关。在这项研究中，我们分析了激肽释放酶抑制剂对 RA 的保护作用及其相关机制。我们分别使用白细胞介素-1β（IL-1β）和热灭活结核分枝杆菌建立了体外和体内 RA 模型。结果表明，激肽释放酶抑制剂减轻了 IL-1β介导的软骨细胞凋亡，并抑制了细胞外基质降解产物（如基质金属蛋白酶[MMP]-3/13 和含有血栓反应蛋白的解整合素金属蛋白酶[ADAMTS]-4/5）的合成在 IL-1β介导的软骨细胞中。此外，激肽释放酶抑制剂通过 NF-κB 通路显著抑制了 IL-1β介导的炎症，同时降低了炎症因子和介质的水平。每天给予激肽释放酶抑制剂可降低 PGE2、TNF-α、IL-1β 和 IL-6 的表达水平。组织化学分析显示，激肽释放酶抑制剂治疗的大鼠与对照组小鼠相比，RA 严重程度降低。总之，激肽释放酶抑制剂通过 NF-κB 通路抑制了软骨细胞中 IL-1β 介导的炎症。激肽释放酶抑制剂给药可显著抑制 RA 的发展，同时减少炎症和凋亡。因此，激肽释放酶抑制剂给药可作为 RA 的候选治疗策略。
