title: Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice.
abstract: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. Fisetin, a polyphenol extracted from fruits and vegetables, has been reported to have anti-inflammatory effects. Our study aimed to investigate the effect of fisetin on OA both in vitro and in vivo. In vitro, chondrocytes were pretreated with fisetin alone or fisetin combined with sirtinol (an inhibitor of SIRT1) for 2h before IL-1β stimulation. Production of NO, PGE2, TNF-α and IL-6 were evaluated by the Griess reaction and ELISAs. The mRNA (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5, Sox-9, aggrecan and collagen-II) and protein expression (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5 and SIRT1) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and SIRT1. SIRT1 activity was quantified with SIRT1 fluorometric assay kit. The in vivo effect of fisetin was evaluated by gavage in mice OA models induced by destabilization of the medial meniscus (DMM). We found that fisetin inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5. Besides, fisetin remarkably decreased IL-1β-induced degradation of Sox-9, aggrecan and collagen-II. Furthermore, fisetin significantly inhibited IL-1β-induced SIRT1 decrease and inactivation. However, the inhibitory effect of fisetin was obvious abolished by sirtinol, suggesting that fisetin exerts anti-inflammatory effects through activating SIRT1. In vivo, fisetin-treated mice exhibited less cartilage destruction and lower OARSI scores. Moreover, fisetin reduced subchondral bone plate thickness and alleviated synovitis. Taken together, these findings indicate that fisetin may be a potential agent in the treatment of OA.
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Shengban
authors.initials: S
authors.lastname: You
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: wys9453@126.com.
authors.forename: Yaosen
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000276:immunology; D005260:Female; D005419:Flavonoids / Q000627:therapeutic use*; D044948:Flavonols; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008592:Menisci, Tibial / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology; D010003:Osteoarthritis / Q000188:drug therapy*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D001549:Benzamides; D005419:Flavonoids; D044948:Flavonols; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D009284:Naphthols; C439060:sirtinol; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C017875:fisetin
keywords: Chondrocyte; Fisetin; Inflammation; Osteoarthritis; SIRT1