Dataset Information

Metformin Mitigates Cartilage Degradation by Activating AMPK/SIRT1-Mediated Autophagy in a Mouse Osteoarthritis Model.

ABSTRACT: Chondrocyte dysfunction is a key mechanism underlying osteoarthritis. Metformin has shown protective effects in many diseases. The present study aimed to investigate the effects of metformin on autophagy and apoptosis in the process of osteoarthritis. A mouse osteoarthritis model was set up by surgically destabilizing medial meniscus in the knee. Intraarticular injection of metformin or vehicle was applied in the right knee for eight weeks. Mouse articular chondrocytes were isolated and passaged for in vitro experiments. Small interfering RNA (siRNA) transfection was used to silence target genes. Western blotting, immunohistochemistry, transmission electron microscopy were used. After eight weeks, metformin restored surgery-induced upregulation of MMP13 and downregulation of type II collagen in the joint cartilage. In cultured primary murine chondrocytes, IL-1? aggravated apoptosis and catabolic response in a dose-dependent manner. In the presence of IL-1?, metformin increased phosphorylated levels of AMPK? and upregulated SIRT1 protein expression, leading to an increase in autophagy as well as a decrease in catabolism and apoptosis. Inactivating AMPK? or inhibiting SIRT1 prevented the augmented autophagy in the presence of metformin. Silencing AMPK?2, but not AMPK?1, reduced SIRT1 expression and downregulated autophagy in cultured chondrocytes. Metformin protects against IL-1?-induced extracellular matrix (ECM) degradation in cultured chondrocytes and in mouse osteoarthritis model through activating AMPK?/SIRT1 signaling. Metformin shed light on the treatment of osteoarthritis.

SUBMITTER: Wang C

PROVIDER: S-EPMC7393141 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Metformin Mitigates Cartilage Degradation by Activating AMPK/SIRT1-Mediated Autophagy in a Mouse Osteoarthritis Model.

Wang Chenzhong C Yao Zhenjun Z Zhang Yueqi Y Yang Yi Y Liu Jinyu J Shi Yi Y Zhang Chi C

Frontiers in pharmacology 20200724

Chondrocyte dysfunction is a key mechanism underlying osteoarthritis. Metformin has shown protective effects in many diseases. The present study aimed to investigate the effects of metformin on autophagy and apoptosis in the process of osteoarthritis. A mouse osteoarthritis model was set up by surgically destabilizing medial meniscus in the knee. Intraarticular injection of metformin or vehicle was applied in the right knee for eight weeks. Mouse articular chondrocytes were isolated and passaged ...[more]

PMID: 32792951

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Project description:BackgroundUncoupled extracellular matrix (ECM) causes cartilage degeneration and osteoarthritis (OA) by suppressing the synthesis and activating the degradation of ECM components. Gingko biloba is a natural Chinese herb with a variety of biological functions; however, the extent to which it can protect against OA and the mechanisms involved are unknown.MethodsIn our study, using bioinformatics tools, we were able to identify an important lactone, bilobalide (BB), from Gingko biloba. In vitro experiments were performed to evaluate the potential therapeutic effects of BB on ECM homeostasis. In vivo experiments were conducted to assess the protection of systemic administration of BB on cartilage degeneration. Molecular mechanisms underlying BB-regulated anti-arthritic role were further explored.ResultsIn interleukin-1β-incubated human chondrocytes, in vitro treatment with BB increased the expression of cartilage anabolic proteins, while inhibiting the activities of ECM degrading enzymes. In a mice model, systemic administration of BB, in vivo, prevented post-traumatic cartilage erosion and attenuated the formation of abnormal osteophytes in the subchondral bone. Mechanistically, the activation of the adenosine 5'-monophosphate-activated protein kinase (AMPK)-sirtuin 1 (SIRT1) signaling pathway was involved in the anti-arthritic effects of BB. In vitro, blocking BB's chondroprotection with the AMPK-specific inhibitor Compound C abrogated it.ConclusionsThese results demonstrated that BB extracted from Gingko biloba regulates ECM balance to prevent OA by activating the AMPK-SIRT1 signaling pathway. This study proposed the monomer BB, a traditional Chinese medicine, as a de novo therapeutic insight for OA. Schematic representation of the experimental design. Based on the bioinformatic analysis, bilobalide (BB), a natural herb Gingko biloba-derived ingredient, was identified as a candidate for treating osteoarthritis. In vitro, BB treatment not only facilitates cartilage extracellular matrix synthesis but also inhibits proteolytic enzyme activities. In vivo intraperitoneal injection of BB improves cartilage degeneration and subchondral bone sclerosis. BB, in particular, had anti-arthritic effects by activating the AMPK-SIRT1 signaling pathway.

Dataset Information

Metformin Mitigates Cartilage Degradation by Activating AMPK/SIRT1-Mediated Autophagy in a Mouse Osteoarthritis Model.

Publications

Metformin Mitigates Cartilage Degradation by Activating AMPK/SIRT1-Mediated Autophagy in a Mouse Osteoarthritis Model.

Similar Datasets

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