title: Cytoprotective and anti-inflammatory effects of melatonin in hydrogen peroxide-stimulated CHON-001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway.
abstract: Melatonin has potent antioxidant, analgesic, and antinociceptive properties. However, the effects of melatonin against oxidative stress-induced cytotoxicity and inflammatory mediators in human chondrocytes remain poorly understood. This study examined the effects and underlying mechanism of melatonin in hydrogen peroxide (H(2) O(2) )-stimulated human chondrocytes and rabbit osteoarthritis (OA) model. Melatonin markedly inhibited hydrogen peroxide (H(2) O(2) )-stimulated cytotoxicity, iNOS, and COX-2 protein and mRNA expression, as well as the downstream products, NO and PGE(2) . Incubation of cells with melatonin decreased H(2) O(2) -induced Sirtuin 1 (SIRT1) mRNA and protein expression. SIRT1 inhibition by sirtinol or Sirt1 siRNA reversed the effects of melatonin on H(2) O(2) -mediated induction of pro-inflammatory cytokines (NO, PGE(2) , TNF-α, IL-1β, and IL-8) and the expression of iNOS, COX-2, and cartilage destruction molecules. Melatonin blocked H(2) O(2) -induced phosphorylation of PI3K/Akt, p38, ERK, JNK, and MAPK, as well as activation of NF-κB, which was reversed by sirtinol and SIRT1 siRNA. In rabbit with OA, intra-articular injection of melatonin significantly reduced cartilage degradation, which was reversed by sirtinol. Taken together, this study shows that melatonin exerts cytoprotective and anti-inflammatory effects in an oxidative stress-stimulated chondrocyte model and rabbit OA model, and that the SIRT1 pathway is strongly involved in this effect.
authors.affiliation: Department of Oral Medicine, School of Dentistry, Wonkwang University, Iksan, Korea.
authors.forename: Hyun-Dae
authors.initials: HD
authors.lastname: Lim
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Kim
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Ko
authors.forename: In-Jong
authors.initials: IJ
authors.lastname: Yoon
authors.forename: Seong-Guk
authors.initials: SG
authors.lastname: Cho
authors.forename: Yang-Hyun
authors.initials: YH
authors.lastname: Chun
authors.forename: Byeong-Jun
authors.initials: BJ
authors.lastname: Choi
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008550:Melatonin / Q000627:therapeutic use*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009284:Naphthols / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010003:Osteoarthritis / Q000188:drug therapy; D011817:Rabbits; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D001549:Benzamides; D016207:Cytokines; D016328:NF-kappa B; D009284:Naphthols; C439060:sirtinol; D006861:Hydrogen Peroxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D056564:Sirtuin 1; D008550:Melatonin