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-1β aggravated apoptosis and catabolic response in a dose-dependent manner. In the presence of IL-1β, metformin increased phosphorylated levels of AMPKα and upregulated SIRT1 protein expression, leading to an increase in autophagy as well as a decrease in catabolism and apoptosis. Inactivating AMPKα or inhibiting SIRT1 prevented the augmented autophagy in the presence of metformin. Silencing AMPKα2, but not AMPKα1, reduced SIRT1 expression and downregulated autophagy in cultured chondrocytes. Metformin protects against IL-1β-induced extracellular matrix (ECM) degradation in cultured chondrocytes and in mouse osteoarthritis model through activating AMPKα/SIRT1 signaling. Metformin shed light on the treatment of osteoarthritis.
Highlights
Osteoarthritis (OA) is a common joint disease characterized by cartilage breakdown and joint tissue deformity (Loeser et al, 2012)
There were no structural changes at the anterior cruciate ligament or meniscus in the knees of the sham group. Both Safranin-O staining and Osteoarthritis Research Society International (OARSI) scores indicted that the surgery induced severer articular cartilage damage and increased the thickness of the synovial membrane compared with the sham group
These results collectively show that the intraarticular injection of metformin mitigated articular cartilage degradation, shown as an increase in type II collagen and a decrease of matrix metallopeptidase 13 (MMP13), with concomitant activation of 5’ adenosine monophosphate-activated protein kinase (AMPK) and silent mating type information regulation homolog1 (SIRT1)
Summary
Osteoarthritis (OA) is a common joint disease characterized by cartilage breakdown and joint tissue deformity (Loeser et al, 2012). Both elevated levels of inflammation and increased expressions of metalloproteinases take part in reducing extracellular matrix of cartilage in the process of OA. Chondrocytes, the primary cell in healthy cartilage, produce cartilaginous matrix, mainly composed of type II collagen and proteoglycans. They produce metalloproteinases to degrade the cartilaginous matrix under disease conditions. Autophagy is proposed to be a promising therapeutic target for OA treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
