{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:19:46Z","timestamp":1789193986511,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,4,10]],"date-time":"2012-04-10T00:00:00Z","timestamp":1334016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hyaluronan (HA) degradation produces small oligosaccharides that are able to increase pro\u2010inflammatory cytokines in rheumatoid arthritis synovial fibroblasts (RASF) by activating both CD44 and the toll\u2010like receptor 4 (TLR\u20104). CD44 and TLR\u20104 stimulation in turn activate the NF\u2010kB that induces the production of pro\u2010inflammatory cytokines. Degradation of HA occurs via two mechanisms: one exerted by reactive oxygen species (ROS) and one controlled by different enzymes in particular hyaluronidases (HYALs). We aimed to investigate the effects of inhibiting HA degradation (which prevents the formation of small HA fragments) on synovial fibroblasts obtained from normal DBA\/J1 mice (NSF) and on synovial fibroblasts (RASF) obtained from mice subjected to collagen induced arthritis (CIA), both fibroblast types stimulated with tumor necrosis factor alpha (TNF\u2010\u03b1). TNF\u2010\u03b1 stimulation produced high mRNA expression and the related protein production of CD44 and TLR\u20104 in both NSF and RASF, and activation of NF\u2010kB was also found in all fibroblasts. TNF\u2010\u03b1 also up\u2010regulated the inflammatory cytokines, interleukin\u20101beta (IL\u20101beta) and interleukin\u20106 (IL\u20106), and other pro\u2010inflammatory mediators, such as matrix metalloprotease\u201013 (MMP\u201013), inducible nitric oxide synthase (iNOS), as well as HA levels and small HA fragment production. Treatment of RASF with antioxidants and specific HYAL1, HYAL2, and HYAL3 small interference RNA (siRNAs) significantly reduced TLR\u20104 and CD44 increase in the mRNA expression and the related protein synthesis, as well as the release of inflammatory mediators up\u2010regulated by TNF\u2010\u03b1. These data suggest that the inhibition of HA degradation during arthritis may contribute to reducing TLR\u20104 and CD44 activation and the inflammatory mediators response. J. Cell. Biochem. 113: 1852\u20131867, 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jcb.24054","type":"journal-article","created":{"date-parts":[[2012,1,10]],"date-time":"2012-01-10T15:04:09Z","timestamp":1326207849000},"page":"1852-1867","source":"Crossref","is-referenced-by-count":64,"title":["The inhibition of hyaluronan degradation reduced pro\u2010inflammatory cytokines in mouse synovial fibroblasts subjected to collagen\u2010induced arthritis"],"prefix":"10.1002","volume":"113","author":[{"given":"Giuseppe 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