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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
Author(s) -
Lim HyunDae,
Kim YoungSuk,
Ko SeokHo,
Yoon InJong,
Cho SeongGuk,
Chun YangHyun,
Choi ByeongJun,
Kim EunCheol
Publication year - 2012
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2012.00991.x
Subject(s) - melatonin , chemistry , oxidative stress , sirtuin 1 , chondrocyte , p38 mitogen activated protein kinases , mapk/erk pathway , pharmacology , endocrinology , medicine , signal transduction , biochemistry , downregulation and upregulation , biology , in vitro , gene
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.