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ABSTRACT:We investigated the feasibility of the intra-articular injection of resveratrol for preventing the progression of existing cartilage degeneration in a mouse model of osteoarthritis (OA). The effects of resveratrol on the expression of silent information regulator 2 type 1 (SIRT1), hypoxia-inducible factor-2a (HIF-2a) and catabolic factors in OA cartilage was explored. OA was induced in the mouse knee via destabilization of the medial meniscus (DMM). Resveratrol was injected weekly into the operated knee beginning 4 weeks after surgery. The OA phenotype was evaluated via histological and immunohistochemical analyses at 8 weeks after DMM. Western blot analysis was performed to identify whether resveratrol modulated the interleukin (IL)-1b-induced expression of HIF-2a in human chondrocytes. Histologically, resveratrol treatment preserved the structural homeostasis of the articular cartilage and the subchondral bone. Following resveratrol injection, the expression of collagen type II was retained, but the expression of inducible nitric oxide synthase and matrix metalloproteinase-13 was reduced in OA cartilage. Moreover, the administration of resveratrol significantly induced the activation of SIRT1 and the inhibition of HIF-2a expression in mouse OA cartilage and in IL-1b-treated human chondrocytes. These findings indicate that the intra-articular injection of resveratrol significantly prevents the destruction of OA cartilage by activating SIRT1 and thereby suppressing the expression of HIF-2a and catabolic factors. Keywords: osteoarthritis; resveratrol; SIRT1; HIF-2a; catabolic factorThe chronic degenerative joint disorder, osteoarthritis (OA) remains the leading cause of long-term disability, and is characterized by abnormal articulation, joint instability, pain and loss of movement.1 Under physiological circumstances, cartilage homeostasis is maintained by an equivalent balance between anabolism and catabolism.2 However, this homeostasis is disrupted in OA, in which catabolism becomes more dominant, leading to the degradation of the cartilaginous extracellular matrix and the eventual destruction of cartilage structure.3,4 The degradation of articular cartilage involves pro-inflammatory cytokine expression, inflammation, increased matrix metalloproteinase (MMP) and aggrecanase expression, decreased extracellular matrix (ECM) synthesis, and chondrocyte apoptosis. Many factors, including biophysical and biochemical activities, have been reported to be responsible for initiating the pathogenesis of OA. Among these factors, hypoxia-inducible factor-2a (HIF-2a) was recently demonstrated to play a key role in the regulation of catabolic reactions in arthritic cartilage. 5,6 HIF-2a (also termed endothelial PAS domain protein-1, EPAS1), belong to the basic helix-loop-helix/ PAS transcription factor family.7 HIF-2a is regulated by its oxygen-dependent degradation and participates in the modulation of the hypoxic response by binding to hypoxia-responsive elements (HREs) in the promoters of target genes. 6,8 In a re...

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Autophagy is an essential cellular homeostasis mechanism that was found to be compromised in aging and osteoarthritis (OA) cartilage. Previous studies showed that resveratrol can effectively regulate autophagy in other cells. The purpose of this study was to determine whether the chondroprotective effect of resveratrol was related to chondrocyte autophagy and to elucidate underlying mechanisms. OA model was induced by destabilization of the medial meniscus (DMM) in 10-week-old male mice. OA mice were treated with resveratrol with/without 3-MA for 8 weeks beginning 4 weeks after surgery. The local intra-articular injection of resveratrol delayed articular cartilage degradation in DMM-induced OA by OARSI scoring systems and Safranin O-fast green. Resveratrol treatment increased Unc-51-like kinase1, Beclin1, microtubule-associated protein light chain 3, hypoxia inducible factor-1α, phosphorylated AMPK, collagen-2A1, Aggrecan expressions, but decreased hypoxia inducible factor-2α, phosphorylated mTOR, matrix metalloproteinases13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 expressions. The effects of resveratrol were obviously blunted by 3-MA except HIF and AMPK. These findings indicate that resveratrol intra-articular injection delayed articular cartilage degeneration and promoted chondrocyte autophagy in an experimental model of surgical DMM-induced OA, in part via balancing HIF-1α and HIF-2α expressions and thereby regulating AMPK/mTOR signaling pathway.

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