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Background: Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder whose progression is modulated by fibroblast-like synoviocytes (FLSs). Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates the activation of other CDKs, and we recently reported that p21 deficiency induces susceptibility to osteoarthritis. Here, we focused on joint inflammation to determine the mechanisms associated with p21 function in synovial and cartilage tissues in RA.Methods: p21-knockout (p21-/-) mice and wild-type C57BL/6 (WT p21+/+) mice were used to establish a collagen antibody-induced arthritis (CAIA) model. The severity of arthritis was evaluated visually, and histological and immunohistological analyses performed 7, 14, and 28 days after injection with a cocktail of five monoclonal antibodies that recognize conserved epitopes on various species of type II collagen. The response of p21 siRNA-treated human RA FLSs to IL-1β stimulation was also determined.Results: Arthritis scores were higher in p21-/- mice than those in p21+/+ mice. More severe and prolonged synovitis of the knee joints and earlier loss of staining and cartilage destruction were observed in p21-/- mice than in p21+/+ mice. p21-/- mice expressed higher levels of IL-1β, F4/80, p-IKKα/β, and MMPs in cartilage and synovial tissues at each time point, except for before injection of the monoclonal antibodies, via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased MMP expression and enhanced IKKα/β phosphorylation in human FLSs.Conclusion: p21-deficient CAIA mice are susceptible to alterations in the RA phenotype, including joint cartilage destruction and severe synovitis, via IL-1β-induced inflammation. Therefore, p21 regulation may constitute a possible strategy for RA treatment. |
