Metformin mitigates cholesterol accumulation via the AMPK/SIRT1 pathway to protect osteoarthritis chondrocytes

In this study, we aim to investigate the effect of metformin on cholesterol synthesis and efflux-related genes in chondrocytes during osteoarthritis (OA) and explore the underlying mechanisms. Primary chondrocytes were harvested from Wistar rat cartilage and divided into control and treatment groups. Chondrocytes in the treatment group were treated with interleukin-1(3 (IL-1(3) mimicking the inflam-matory environment of osteoarthritis. Subsequently, RT-qPCR, Western blotting, immunofluorescence staining, and Cell Counting Kit-8 (CCK-8) were conducted. Significant reductions in phosphorylated AMP -activated protein kinase (p-AMPK) and silent information regulator 1 (SIRT1) protein expression were observed in both human OA chondrocytes and cultured primary murine chondrocytes treated with IL-1(3, while AMP-activated protein kinase (AMPK) was not inhibited. Moreover, in the presence of IL-1(3, metformin significantly increased the expression of p-AMPK and SIRT1 at the protein and mRNA level. Meanwhile, metformin could reverse IL-1(3-induced cartilage extracellular matrix degradation in chon-drocytes from the rat model of OA (treated by IL-(3) by activating the AMPK/SIRT1 pathway. Moreover, metformin activated AMPK and SIRT1, mediated by the activation of SREBP-2 and HMGCR in OA chon-drocytes. Inhibiting AMPK/SIRT1 activity by its specific inhibitor could suppress IL-1(3-induced expres-sion of LXRc, ABCA1 and ApoA1 and cholesterol efflux. Thus, metformin inhibits cholesterol synthesis and promotes cholesterol efflux by activating the AMPK/SIRT1 pathway in OA chondrocytes. This study improves our understanding of the effect of metformin on cholesterol accumulation in OA chondrocytes.(c) 2022 Published by Elsevier Inc.