Abstract
Osteoarthritis (OA) is considered the most frequent degenerative disease and is characterized by cartilage degradation and synovial inflammation. Fibroblast-like synoviocytes (FLSs) are vital to synovial inflammation in OA. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and hyperinsulinemia (HINS) and has been demonstrated to be an independent risk factor for OA. Autophagy is involved in the processes of various inflammatory diseases, and autophagy inhibition can stimulate OA development. Thus, we aimed to investigate the role of insulin in the inflammatory phenotype and autophagy of FLSs in OA. The data showed that cell viability and proinflammatory cytokine production in FLSs were both increased after insulin stimulation. We also found that high insulin could promote macrophage infiltration and chemokine production but inhibited autophagy in FLSs. To further explore the potential mechanisms, the effects of insulin on PI3K/Akt/mTOR and NF-ĸB signaling activation were evaluated. The results indicated that insulin activated PI3K/Akt/mTOR/NF-ĸB signaling, and the above-mentioned inflammatory responses, including autophagy inhibition, were notably attenuated by specific signaling inhibitors in the presence of high insulin. Moreover, the data showed that a positive feedback loop existed between proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) and PI3K/mTOR/Akt/NF-ĸB signaling in FLSs, and insulin enhanced this feedback loop to accelerate OA progression. Our study suggests that insulin may be a novel therapeutic strategy for OA prevention and treatment in the future.
Highlights
Osteoarthritis (OA) is an underlying cause of disability and the most frequently occurring degenerative joint disease [1]
A previous study suggested that fibroblast-like synoviocytes (FLSs) are vital for osteoarthritis pathogenesis and that synoviocyte hyperplasia and abnormal synoviocyte proinflammatory cytokine production were both important pathological hallmarks of OA [2,3,4,5]
Based on the above-mentioned research, we suggest that insulin is involved in a positive feedback loop between IL-1β/IL-6/Tumor necrosis factor (TNF)-α and PI3K/mTOR/Akt/Nuclear factor–kappa B (NF-ĸB) signaling in FLSs
Summary
Osteoarthritis (OA) is an underlying cause of disability and the most frequently occurring degenerative joint disease [1]. The classical nuclear factor-kappa B (NF-ĸB) signaling pathway has been reported to be crucial for inducing the expression of various proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) and is considered a potential target in OA progression. These downstream cytokines (e.g., IL-1β, IL-6, and TNF-α) are important inducers of NF-ĸB signaling. Proinflammatory cytokines induced by the NF-ĸB signaling pathway (e.g., IL-1, IL-6, and TNF-α) could lead to matrix metalloproteinase (MMP) production, causing articular cartilage breakdown and bone resorption in OA progression. The potential role of the NF-ĸB signaling pathway and the targets of inflammatory responses in FLSs were explored in this study
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