| First Author | Takashima Y | Year | 2021 |
| Journal | Sci Rep | Volume | 11 |
| Issue | 1 | Pages | 12516 |
| PubMed ID | 34131243 | Mgi Jnum | J:313911 |
| Mgi Id | MGI:6720149 | Doi | 10.1038/s41598-021-92055-9 |
| Citation | Takashima Y, et al. (2021) Susceptibility of cyclin-dependent kinase inhibitor 1-deficient mice to rheumatoid arthritis arising from interleukin-1beta-induced inflammation. Sci Rep 11(1):12516 |
| abstractText | 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)-1beta 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-1beta, TNF-alpha, F4/80, CD86, p-IKKalpha/beta, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1beta-induced NF-kB signaling. IL-1beta stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKalpha/beta and IkappaBalpha 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-1beta, IL-6, and TNF-alpha. |
