A novel role for endoplasmic reticulum protein ERp72 in the pathogenesis of autoantibody-induced arthritis

Abstract

Objective The family of protein disulphide isomerases (PDIs) is a group of oxidoreductases that catalyze the oxidation, reduction and isomerization of disulphide bonds. Recent studies have shown that overexpression of one of the family enzymes, ERp46, potentiates arthritis severity, suggesting that the PDI family participates in arthritis pathogenesis. This study investigated the role of another PDI member, ERp72, in autoantibody-induced arthritis. Methods Using the Cre-LoxP method, a mouse strain lacking ERp72 (ERp72−/− mice) was generated. Autoantibody-induced arthritis was induced in both ERp72−/− and ERp72+/+ control mice by injecting serum from K/BxN mice. The synovial inflammation severity was evaluated by joint diameter measurements and histological analysis. Proinflammatory cytokines expression in joint tissue and plasma was assessed by quantitative real-time PCR and ELISA. Results : The absence of ERp72 in the joints, white blood cells, spleen, thymus, and bone marrow of ERp72−/− mice was confirmed. In the K/BxN serum transfer-induced arthritis (STIA) model, ERp72−/− mice exhibited exacerbated arthritis compared to ERp72+/+ mice, with greater joint swelling, bone and cartilage erosion, and synovial inflammation. Furthermore, ERp72–/– mice exhibited increased expression of IL-1β, IL-6 and TNF-α in inflamed joint tissues and higher IL-6 levels in plasma. Conversely, IL-10 levels were lower in ERp72–/– mice inflamed joints than in ERp72+/+ mice. Notably, the basal TNF-α level in the blood of ERp72−/− mice was significantly higher than in ERp72+/+ mice. Conclusion ERp72 plays a key role in the negative regulation of autoantibody-induced arthritis.