Interleukin‐21 induces migration and invasion of fibroblast‐like synoviocytes from patients with rheumatoid arthritis

Summary Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone erosion. Fibroblast‐like synoviocytes (FLS) play a pivotal role in RA pathogenesis through aggressive migration and matrix invasion, and certain proinflammatory cytokines may affect synoviocyte invasion. Whether interleukin (IL)‐21 influences this process remains controversial. Here, we evaluated the potential regulatory effect of IL‐21 on the migration, invasion and matrix metalloproteinase (MMP) expression in RA‐FLS. We found that IL‐21 promoted the migration, invasion and MMP (MMP‐2, MMP‐3, MMP‐9, MMP‐13) production in RA‐FLS. Moreover, IL‐21 induced activation of the phosphoinositide 3‐kinase (PI3K), signal transducer and activator of transcription‐3 (STAT‐3) and extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT‐3 inhibitor STA‐21 and ERK1/2 inhibitor PD98059] attenuated IL‐21‐induced migration and secretion of MMP‐3 and MMP‐9. In conclusion, our results suggest that IL‐21 promotes migration and invasion of RA‐FLS. Therefore, therapeutic strategies targeting IL‐21 might be effective for the treatment of RA.