Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Emergency Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
Chem Biol Interact. 2024 Feb 25;390:110890. doi: 10.1016/j.cbi.2024.110890. Epub 2024 Jan 24.
Osteoarthritis (OA) is the most common type of arthritis and is an age-related joint disease that is particularly prevalent in subjects over 65 years old. The chronic rise of senescent cells has a close correlation with age-related diseases such as OA, and the senescence-associated secretory phenotype (SASP) is implicated in OA cartilage degeneration pathogenesis. Sirtuin 6 (SIRT6) is likely to be a key senescence-related regulator. Fisetin (FST) is a natural flavonol of the flavonoid family that is recommended as a senolytic drug to extend health and lifespan. However, the potential chondroprotective effects of FST on OA rats are largely unclarified. The aim of this study is to investigate the ameliorative effects of FST on OA joint cartilage and the relationship with SIRT6 and the detailed mechanisms from anti-inflammatory and anti-senescent perspectives. Rats were subjected to destabilization of the medial meniscus (DMM) surgery as a means of inducing the experimental OA model in vivo. Chondrocytes treated with IL-1β were utilized for mimicking the OA cell model in vitro. Intra-articular injection of FST, OSS_128,167 (OSS, SIRT6 inhibitor), and MDL800 (MDL, SIRT6 agonist) in vivo or administering them in IL-1β-induced rat chondrocytes in vitro were performed in order to determine the effects FST has on OA and the link with SIRT6. This study found SIRT6 level to be negatively correlated with OA severity. SIRT6 downregulation was validated in the joint cartilages of DMM rats and IL-1β-treated chondrocytes. It was also notably demonstrated that FST can activate SIRT6. Both the administration of FST and activation of SIRT6 using MDL were found to rescue cartilage erosion, decrease extracellular matrix (ECM) degradation, prevent cartilage from apoptosis, and improve detrimental senescence-related phenotype. The alleviative effects of FST against inflammation, ECM degradation, apoptosis, and senescence in IL-1β-stimulated chondrocytes were also confirmed. SIRT6 loss occurs in articular cartilage in OA pathogenesis, which is linked to aging. FST attenuates injury-induced aging-related phenotype changes in chondrocytes through the targeting of SIRT6.
骨关节炎（OA）是最常见的关节炎类型，是一种与年龄相关的关节疾病，尤其在 65 岁以上的人群中较为普遍。衰老细胞的慢性增加与 OA 等与年龄相关的疾病密切相关，衰老相关分泌表型（SASP）与 OA 软骨退变的发病机制有关。Sirtuin 6（SIRT6）可能是关键的衰老相关调节因子。非瑟酮（FST）是一种黄酮类家族的天然类黄酮，被推荐为一种衰老细胞清除剂，以延长健康和寿命。然而，FST 对 OA 大鼠的潜在软骨保护作用在很大程度上仍不清楚。本研究旨在探讨 FST 对 OA 关节软骨的改善作用及其与 SIRT6 的关系，并从抗炎和抗衰老的角度探讨其详细机制。通过内侧半月板不稳定（DMM）手术在体内诱导实验性 OA 模型，将大鼠的软骨细胞用白细胞介素-1β（IL-1β）处理以模拟 OA 细胞模型。体内给予 FST、OSS_128,167（OSS，SIRT6 抑制剂）和 MDL800（MDL，SIRT6 激动剂），或在体外给予 IL-1β诱导的大鼠软骨细胞，以确定 FST 对 OA 的影响及其与 SIRT6 的关系。本研究发现 SIRT6 水平与 OA 严重程度呈负相关。在 DMM 大鼠的关节软骨和 IL-1β处理的软骨细胞中验证了 SIRT6 的下调。此外，还发现 FST 可以激活 SIRT6。给予 FST 和使用 MDL 激活 SIRT6 均能挽救软骨侵蚀，减少细胞外基质（ECM）降解，防止软骨细胞凋亡，并改善有害的衰老相关表型。还证实了 FST 在抑制 IL-1β刺激的软骨细胞炎症、ECM 降解、凋亡和衰老方面的缓解作用。SIRT6 在 OA 发病机制中的关节软骨中丢失，这与衰老有关。FST 通过靶向 SIRT6 减轻损伤诱导的软骨细胞衰老相关表型变化。
Chem Biol Interact. 2024-2-25
Drug Des Devel Ther. 2019-10-9
Nat Commun. 2022-12-10
Int Immunopharmacol. 2024-10-25
Naunyn Schmiedebergs Arch Pharmacol. 2025-1-9
Pharmaceuticals (Basel). 2024-8-30
Biomedicines. 2024-8-26
Signal Transduct Target Ther. 2024-9-18
Zotero 插件