BioScience Trends. 2018;12(6):605-612. (DOI: 10.5582/bst.2018.01263)

Protective effects of metformin against osteoarthritis through upregulation of SIRT3-mediated PINK1/Parkin-dependent mitophagy in primary chondrocytes.

Wang CZ, Yang Y, Zhang YQ, Liu JY, Yao ZJ, Zhang C


Mitochondrial damage is involved in the pathogenesis of osteoarthritis. Metformin, one of the most common prescriptions for patients with type 2 diabetes, can reportedly activate Sirtuin 3 (SIRT3) expression which protects mitochondria from oxidative stress. In this study, we investigated the inhibitory property of metformin on mitochondrial damage by focusing on the interleukin-1 beta (IL-1β)-stimulated osteoarthritis model by using primary murine chondrocytes. Our results demonstrated that SIRT3 was downregulated in chondrocytes under IL-1β stimulation, where its expression was positively correlated with mitochondrial damage and reactive oxygen species (ROS) production. Metformin treatment upregulated SIRT3 expression and mitigated loss of cell viability and decreased the generation of mitochondria-induced ROS in chondrocytes stimulated with IL-1β. Metformin also attenuated IL-1β-induced expressions of catabolic genes such as matrix metalloproteinase-3 (MMP3) and MMP13 and enhanced the anabolic indicator Collagen Ⅱ. These effects were mediated by phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1)/Parkin-dependent mitophagy and the autophagic elimination of damaged mitochondria. Further, the SIRT3 inhibitor 3-TYP effectively inhibited the initiation of mitophagy, as decreased expression of PINK1 and Parkin, decreased the LC3II/LC3I, enhanced the expression of MMP3 and MMP13, and decreased the expression of Collagen Ⅱ. Overall, our findings provide evidence that metformin suppresses IL-1β-induced oxidative and osteoarthritis-like inflammatory changes by enhancing the SIRT3/PINK1/Parkin signaling pathway, thereby indicating metformin's potential in prevention and treatment of osteoarthritic joint disease.

KEYWORDS: Osteoarthritis, mitophagy, SIRT3

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