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Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21<jats:sup>\u2212\/\u2212<\/jats:sup>) (<jats:italic>n<\/jats:italic>\u2009=\u200916) and wild type C57BL\/6 (p21<jats:sup>+\/+<\/jats:sup>) mice (<jats:italic>n<\/jats:italic>\u2009=\u200916) 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 (<jats:italic>n<\/jats:italic>\u2009=\u20095 per group) to interleukin (IL)-1\u03b2 stimulation was determined in vitro. Arthritis scores were higher in p21<jats:sup>\u2212\/\u2212<\/jats:sup> mice than in p21<jats:sup>+\/+<\/jats:sup> mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21<jats:sup>\u2212\/\u2212<\/jats:sup> mice compared to p21<jats:sup>+\/+<\/jats:sup> mice. p21<jats:sup>\u2212\/\u2212<\/jats:sup> mice expressed higher levels of IL-1\u03b2, TNF-\u03b1, F4\/80, CD86, p-IKK\u03b1\/\u03b2, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1\u03b2-induced NF-kB signaling. IL-1\u03b2 stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKK\u03b1\/\u03b2 and I\u03baB\u03b1 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\u00a0regulatory role in inflammatory cytokine production including IL-1\u03b2, IL-6, and TNF-\u03b1.<\/jats:p>","DOI":"10.1038\/s41598-021-92055-9","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T10:04:25Z","timestamp":1623751465000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Susceptibility of cyclin-dependent kinase inhibitor 1-deficient mice to rheumatoid arthritis arising from interleukin-1\u03b2-induced inflammation"],"prefix":"10.1038","volume":"11","author":[{"given":"Yoshinori","family":"Takashima","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihisa","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Tsubosaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Kamenaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Kuroda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shingo","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Kuroda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"92055_CR1","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1002\/art.1780310803","volume":"31","author":"M Rooney","year":"1988","unstructured":"Rooney, M. et al. 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