Susceptibility of cyclin-dependent kinase inhibitor 1-deficient mice to rheumatoid arthritis arising from interleukin-1β-induced inflammation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-06-15

AUTHORS

Yoshinori Takashima, Shinya Hayashi, Koji Fukuda, Toshihisa Maeda, Masanori Tsubosaka, Tomoyuki Kamenaga, Kenichi Kikuchi, Masahiro Fujita, Yuichi Kuroda, Shingo Hashimoto, Naoki Nakano, Tomoyuki Matsumoto, Ryosuke Kuroda

ABSTRACT

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. More... »

PAGES

12516

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-021-92055-9

DOI

http://dx.doi.org/10.1038/s41598-021-92055-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1138865014

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/34131243


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