Fisetin suppresses chondrocyte senescence and attenuates osteoarthritis progression by targeting SIRT6

Abstract Background Osteoarthritis (OA), the most common type of arthritis, is a highly prevalent age-related joint disease particularly in subjects over 65 years old. The chronic rise of senescent cells closely correlates with age-related diseases including OA, and the senescence(definition)-associated secretory phenotype (SASP) is implicated in the pathogenesis of OA cartilage degeneration. Sirtuin 6 (SIRT6) is probable to be a key senescence-related regulator. Fisetin (FST), a natural flavonol of the flavonoid family, is recommended to be a senolytic that extends health and lifespan. However, the potential chondroprotective effects of FST on OA rats remain largely unclarified. This study aimed to investigate the ameliorative effects of FST on OA joint cartilage and the relationship with SIRT6, and the detailed mechanisms from both anti-inflammatory and anti-senescent perspectives. Methods Rats were subjected to destabilization of the medial meniscus (DMM) surgery to induce the experimental OA model in vivo. Chondrocytes treated with IL-1β were utilized to mimic the OA cell model in vitro. Intra-articular injection of FST, OSS_128167 (OSS, SIRT6 inhibitor), and MDL800 (MDL, SIRT6 agonist) in vivo or incubation with IL-1β-induced rat chondrocytes in vitro were performed to determine the effects of FST on OA and the link with SIRT6. Results SIRT6 level was negatively correlated with OA severity. SIRT6 downregulation was validated in joint cartilages of DMM rats and IL-1β-treated chondrocytes. Of note, We demonstrated FST could activate SIRT6. Both the administration of FST and activation of SIRT6 using MDL rescued cartilage erosion, decreased extracellular matrix (ECM) degradation, prevented cartilage from apoptosis, and improved detrimental senescence-related phenotype. The alleviative effects of FST against inflammation, ECM degradation, apoptosis, and senescence were also confirmed in IL-1β-stimulated chondrocytes. Conclusion SIRT6 loss occurs in articular cartilage in the pathogenesis of OA, which is linked to aging. FST attenuates injury-induced aging-related phenotype changes in chondrocytes by targeting SIRT6.