Local intra-articular injection of resveratrol delays cartilage degeneration in C57BL/6 mice by inducing autophagy via AMPK/mTOR pathway

• Published in: Journal of pharmacological sciences Vol. 134; no. 3; pp. 166 - 174
• Main Authors: Qin, Na, Wei, Liwei, Li, Wuyin, Yang, Wei, Cai, Litao, Qian, Zhuang, Wu, Shufang
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 01.07.2017; Elsevier
• Subjects: AMP activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Autophagy; Autophagy - drug effects; Autophagy - genetics; Cartilage - pathology; Chondrocytes - physiology; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Injections, Intra-Articular; Male; Mammalian target of rapamycin; Mice, Inbred C57BL; Osteoarthritis; Osteoarthritis - drug therapy; Osteoarthritis - pathology; Resveratrol; Signal Transduction - drug effects; Signal Transduction - physiology; Stilbenes - administration & dosage; Stilbenes - pharmacology; TOR Serine-Threonine Kinases - metabolism; DMM; AMP activated protein kinase; Autophagy; ADAMTS5; HIF-1; OA; MMP13; Resveratrol; Mammalian target of rapamycin; mTOR; AMPK; 3-MA; ULK1; Osteoarthritis; LC3
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2017.06.002

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.