Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis

Abstract

Osteoarthritis (OA) is a degenerative joint disease mainly characterized by cartilage degradation. Interleukin-1β (IL-1β) contributes to OA pathogenesis by enhancing oxidative stress and inflammation. Melatonin reportedly elicits potent protection against OA. However, the role of melatonin and underlying mechanism in IL-1β-stimulated chondrocytes remain largely unclear. In this study, we found that melatonin inhibited IL-1β-induced toxicity and sirtuin 1 (Sirt1) enhancement in human chondrocytes. Melatonin reduced the IL-1β-increased nicotinamide phosphoribosyltransferase (NAMPT) expression and the NAD+ level in chondrocytes in a Sirt1-dependent manner. In turn, the inhibitory effect of melatonin on Sirt1 was mediated by NAMPT. Moreover, melatonin suppressed IL-1β-induced Sirt1-mediated matrix metalloproteinase (MMP)-3 and MMP-13 production. Melatonin also decreased the Sirt1-steered nuclear factor of activated T cells 5 (NFAT5) expression in IL-1β-challenged chondrocytes. NFAT5 depletion mimicked the suppressive effects of melatonin on IL-1β-elevated production of inflammatory mediators, including tumor necrosis factor-α (TNF-α), IL-1β, prostaglandin E2 (PGE2), and nitric oxide (NO) in chondrocytes. TNF-α, IL-1β, PGE2, or NO decrease caused the similar reduction of MMP-3 and MMP-13 by melatonin in IL-1β-insulted chondrocytes. Highly consistent with in vitro findings, in vivo results demonstrated that melatonin repressed the expression of relevant genes in rat OA pathogenesis in anterior cruciate ligament transection model. Overall, these results indicate that melatonin effectively reduced IL-1β-induced MMP production by inhibiting Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes, suggesting melatonin as a potential therapeutic alternative for chondroprotection of OA patients.

Circ_0136474 and MMP‐13 suppressed cell proliferation by competitive binding to miR‐127‐5p in osteoarthritis

“…Based on latest research, miR‐27b was identified as a potential regulator of MMP‐13 expression in human chondrocytes by demonstrating its modulation by IL‐1β in human chondrocytes . Furthermore, it was reported that IL‐1β and TNF‐α were the two most potent catabolic factors that increased the production of inflammatory mediators and the expression of MMPs in chondrocytes . miR‐181b was a negative regulator of cartilage development and in vitro attenuation reduced MMP‐13 expression while inducing collagen type II expression .…”

“…28 Furthermore, it was reported that IL-1β and TNF-α were the two most potent catabolic factors that increased the production of inflammatory mediators and the expression of MMPs in chondrocytes. 29…”

Melatonin rescued interleukin 1β-impaired chondrogenesis of human mesenchymal stem cells

“…Thirdly, we did not fully excavate the underlying mechanisms of MLT’s effect. Guo et al [ 37 ] demonstrate that MLT inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate OA. However, in the chondrogenic process with IL-1β presence, MLT’s role is still not clear.…”

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

“…Together these data provide a rationale for questioning the role of CR alteration in OA. Following the pioneering description of BMAL1/CLOCK in chondrocytes, it has been subsequently demonstrated that inflammatory cytokines such as IL-1β, conversely to TNF-alpha, severely affects the expression of BMAL1/CLOCK through functional interference with NF-kB (Guo et al, 2017 ). More recently, it has also been demonstrated that BMAL1, which is essential to maintain the differentiated phenotype of chondrocytes through its interaction with a large number of TGF-β signaling members (Akagi et al, 2017 ), was repressed in OA and associated with a switch of catabolic phenotype (Snelling et al, 2016 ).…”