摘要：We recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21
−/−) (
n = 16) and wild type C57BL/6 (p21
+/+) mice (
n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (
n = 5 per group) to interleukin (IL)-1β stimulation was determined in vitro. Arthritis scores were higher in p21
−/− mice than in p21
+/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21
−/− mice compared to p21
+/+ mice. p21
−/− mice expressed higher levels of IL-1β, TNF-α, F4/80, CD86, p-IKKα/β, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/β and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1β, IL-6, and TNF-α.
