IGF2BP2 regulates the inflammation of fibroblast-like synoviocytes via GSTM5 in rheumatoid arthritis

Abstract

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease with an unknown etiology. RA cannot be fully cured and requires lengthy treatment, which causes a great burden on both individuals and society. Due to the lack of specific drugs available for treating RA, exploring a key new therapeutic target for RA is currently an important task. Activated fibroblast-like synoviocytes (FLSs) are key participants in the progression of rheumatoid arthritis, which release interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α that cause abnormal inflammatory reaction in the synovium. Previous study has highlighted the correlation of m6A reader IGF2BP2 and inflammation-related diseases in human. However, the role of IGF2BP2 in inflammatory reaction of FLSs in RA progression has not been assessed. In this study, IGF2BP2 expression was decreased in the synovial tissues from RA patients and collagen induced arthritis (CIA) rats. Intra-articular injection with IGF2BP2 overexpressive adeno-associated virus relieved paw swelling, synovial hyperplasia and cartilage destruction in CIA rats. IGF2BP2 overexpression also inhibited lipopolysaccharide (LPS)-mediated RA-FLSs migration and invasion accompanied by the decreased levels of inflammatory factors in vitro. Conversely, IGF2BP2 suppression promoted RA-FLSs migration and invasion with an elevated level of inflammatory factors in vitro. Sequencing result showed that GSTM5, a key antioxidant gene, was the target mRNA of IGF2BP2. Further experiments demonstrated that IGF2BP2 strengthened the stability of GSTM5 mRNA leading to weakened inflammatory reaction and reduced expression of MMP9 and MMP13. Therefore, IGF2BP2-GSTM5 axis may be a potential therapeutic target for RA treatment.