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-1b aggravated apoptosis and catabolic response in a dose-dependent manner. In the presence of IL-1b, metformin increased phosphorylated levels of AMPKa and upregulated SIRT1 protein expression, leading to an increase in autophagy as well as a decrease in catabolism and apoptosis. Inactivating AMPKa or inhibiting SIRT1 prevented the augmented autophagy in the presence of metformin. Silencing AMPKa2, but not AMPKa1, reduced SIRT1 expression and downregulated autophagy in cultured chondrocytes. Metformin protects against IL-1b-induced extracellular matrix (ECM) degradation in cultured chondrocytes and in mouse osteoarthritis model through activating AMPKa/SIRT1 signaling. Metformin shed light on the treatment of osteoarthritis.

Metformin attenuates osteoclast-mediated abnormal subchondral bone remodeling and alleviates osteoarthritis via AMPK/NF-κB/ERK signaling pathway

“…The increased prevalence of OA in patients with type 2 diabetes suggests that OA may be associated with energy metabolism [ 36 ]. Multiple studies have shown that Met, in addition to regulating blood glucose, is able to regulate bone remodeling and it exhibits osteogenic and chondroprotective effects [ 37 – 39 ]. However, little is known regarding the effects of Met on osteoclast formation and it potential as an OA treatment.…”

Metformin Attenuates Monosodium-Iodoacetate-Induced Osteoarthritis via Regulation of Pain Mediators and the Autophagy–Lysosomal Pathway

“…Autophagy is an essential cellular and molecular mechanism that is important for maintaining cellular homeostasis [ 39 ], and it has been reported that autophagy is reduced in the cartilage of OA patients [ 40 ]. Recently Wang and colleagues reported the protective effects of metformin against osteoarthritis through the activation of autophagy [ 41 , 42 ]. In this study, our result confirmed the therapeutic effects of metformin through the activation of autophagy.…”

LncRNA CRNED Hinders the Progression of Osteoarthritis by Epigenetic Regulation of DACT1

“…Chondrocytes can produce cartilage extracellular matrix rich in collagen (mainly type II collagen) and proteoglycans. Under pathological conditions, chondrocytes can also produce mechanisms such as metalloproteinases to degrade cartilage matrix [25]. In addition, after the occurrence of OA, chondrocyte functions including proliferation and secretion have undergone many changes [26].…”