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.

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…Melatonin also interfered with H 2 O 2 -induced phosphorylation of PI3K/Akt p38 and MAPK, as well as activation of NF-B, which was reversed by sirtinol and SIRT1 siRNA. These findings are consistent with the idea that the cytoprotective and anti-inflammatory properties of melatonin involve the dynamic action of the SIRT1 pathway (Lim et al, 2012). In addition, in cadmium-induced hepatotoxicity, melatonin exerts positive effects, which are associated with enhanced mitochondrial biogenesis through a SIRT1-dependent PGC-1␣ pathway.…”

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

“…Consistent with previous reports, Li and colleagues, reported that resveratrol preserved cartilage homeostasis by inhibiting the catabolic effects of HIF-2α expression [30•]. A similar study by Lim et al concluded that melatonin bestows cytoprotective and anti-inflammatory effects via the SIRT1 pathway in rabbit model of OA [31]. Moreover, administering Sirtinol (a Sirt1 inhibitor) reversed the melatonin-dependent protective effect, confirming the role of Sirt1 in mediating this process.…”

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

“…Correspondingly, additional in vivo studies (14) demonstrated that Sirt1 exerts an anti-inflammatory effect in cartilage during OA. Moreover, mechanistic studies have provided further support that SIRT1 promotes chondrocyte survival through various pathways (15)(16)(17)(18)(19)-in particular, deacetylation of p65/ RelA-which reduces iNOS gene expression after IL-1b challenge of chondrocytes (20).…”