Melatonin Prevents Cartilage Degradation in Early-Stage Osteoarthritis Through Activation of miR-146a/NRF2/HO-1 Axis

Abstract

Reactive oxygen species (ROS) are implicated in induction of inflammatory response and cartilage degradation in osteoarthritis (OA). Melatonin has been shown to improve the chondrogenic differentiation and promote cartilage matrix synthesis in mesenchymal stem cells. However, the underlying mechanisms of melatonin-regulated antioxidant activity in OA cartilage are not known. The aim of this study was to explore the effect of melatonin on nuclear factor-erythroid 2-related factor 2 (NRF2), a key antioxidant transcription factor, and its target antioxidant genes in early-stage OA cartilage. Primary chondrocytes were isolated from rats with surgically induced OA. In vitro treatment of melatonin significantly increased cartilage matrix synthesis and upregulated antioxidant enzymes, mainly heme oxygenase 1 (HO-1), while decreasing matrix degradation enzymes and intracellular ROS. In vivo intraarticular injection of melatonin effectively ameliorated cartilage degeneration in an experimental rat OA model. Inhibition of melatonin membrane receptors by Luzindole or 4-P-PDOT reversed the beneficial effects of melatonin on cartilage matrix synthesis, implying that melatonin receptor-mediated pathway is involved in its anti-arthritic effects. Interestingly, melatonin showed no significant effect on the mRNA level of Nrf2 but significantly increased its protein level. Silencing of Nrf2 or HO-1 expression abolished the protective effects of melatonin, as shown by increased ROS levels and matrix degradation enzyme expression. Microarray assays revealed that miR-146a, a predicted target for Nrf2, was significantly upregulated in OA chondrocytes but was markedly reduced by melatonin treatment. Overexpression of miR-146a diminished the protective effects of melatonin by inhibiting NRF2 expression and aggravating OA-induced cartilage degradation. These findings demonstrate that melatonin supports the anabolic metabolism of cartilage matrix in OA chondrocytes by enhancing the protein levels of NRF2 via suppressing miR-146a. Melatonin-mediated activation of the NRF2/HO-1 axis prevents cartilage degeneration and represents a promising therapeutic target for treatment of early-stage OA.

Tempol alleviates acute lung injury by affecting glutathione synthesis through Nrf2 and inhibiting ferroptosis in lung epithelial cells

“…[ 37 ] Enhancement of Nrf2 signaling may improve catalase and superoxide dismutase expression and prevent ROS overproduction. [ 38 ] However, Nrf2 deficiency exacerbates the neuronal death associated with the disease, increasing neuroinflammation and protein aggregation. [ 39 ] In this study, we found that overexpression of Nrf2 and Tempol synergistically alleviates LPS‐induced oxidative stress in BEAS‐2B cells and inhibits cell ferroptosis.…”

Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

“…Our previous studies systematically reported the pivotal role of the melatonin‐SIRT1 axis in controlling the fate of chondrocytes and antagonizing OA. [ 63 ] Melatonin has a hepatoprotective effect on mitochondrial‐derived free radicals‐stimulated autophagic cell death, which is dependent on SIRT3/SOD2 pathway activation. [ 64 ] Furthermore, the Warburg effect during lung cancer development could be reversed by melatonin‐SIRT3‐stimulated mitochondrial membrane polarization and the activities of complex I and IV in ETC.…”

Therapeutic targets and potential delivery systems of melatonin in osteoarthritis

“…Melatonin acts as an effective antioxidant, regulating the homeostasis of the cartilage matrix through the Nrf2 signaling pathway. This is evidenced by the increased expression of Nrf2 in melatonin-treated chondrocytes, which led to a reduction of intracellular ROS levels and a significant elevation in the expression of SOD1, SOD2, CAT, and HO-1 ( 136 ). The expression of Nrf2 and antioxidant enzymes could be significantly inhibited by miR-146a, which was markedly elevated in OA chondrocyte.…”

“…The expression of Nrf2 and antioxidant enzymes could be significantly inhibited by miR-146a, which was markedly elevated in OA chondrocyte. Moreover, overexpression of miR-146a reduced the level of Nrf2, thereby diminishing the protective effects of melatonin in articular cartilage of rats ( 136 ).…”