Ding Li, Lin Huijun, Ma Zhidong, He Yong, Ding Sheng, Zhang Kaile, Zhang Jiechao, Li Wenyao, Xiao Lianbo
Department of Orthopedic, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai 200052, China.
School of Materials Science and Engineering, Shanghai University of Engineering Science, Shanghai 201620, China; The Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai 200233, China.
Mol Immunol. 2025 Mar;179:9-17. doi: 10.1016/j.molimm.2025.01.013. Epub 2025 Feb 4.
Stigmasterol (Stig), a phytosterol with anti-inflammatory and antioxidant properties, has been shown to have potential therapeutic effects. In this study, we aimed to investigate whether Stig mitigates rheumatoid arthritis (RA) progression by reducing chondrocyte injury. A mouse model of RA was established by intradermally injecting type II collagen into the tail roots of mice. The arthritic score and spleen index were measured in RA mice to assess the effects of Stig on RA progression. Lipopolysaccharide (LPS)-treated chondrocytes were used as a cellular model of RA. The roles of Stig in chondrocyte viability, proliferation, migration, inflammation, and injury were assessed using Cell Counting Kit-8, EdU, Transwell assays, quantitative real-time PCR, and western blotting, respectively. The results demonstrated that Stig exhibited no significant cytotoxicity in CHON-001 chondrocytes. Interestingly, it effectively inhibited LPS-induced apoptosis and increased cell viability, proliferation, and migration. Stig also alleviated LPS-induced pro-inflammatory responses and CHON-001 cell injury. Mechanistically, Stig activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which led to the inactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome and a subsequent decrease in CHON-001 cell pyroptosis. However, the protective effects of Stig were abrogated by ML385, a specific inhibitor Nrf2. Stig treatment further improved the clinical severity in RA mice. In summary, Stig reduces LPS-induced chondrocyte injury and mitigates RA progression by inhibiting Nrf2/NLRP3-mediated pyroptosis, offering a potential therapeutic approach for RA.
豆甾醇（Stig）是一种具有抗炎和抗氧化特性的植物甾醇，已显示出具有潜在的治疗作用。在本研究中，我们旨在探讨Stig是否通过减少软骨细胞损伤来减轻类风湿性关节炎（RA）的进展。通过向小鼠尾根部皮内注射II型胶原建立RA小鼠模型。测量RA小鼠的关节炎评分和脾脏指数，以评估Stig对RA进展的影响。用脂多糖（LPS）处理的软骨细胞作为RA的细胞模型。分别使用细胞计数试剂盒-8、EdU、Transwell实验、定量实时PCR和蛋白质印迹法评估Stig在软骨细胞活力、增殖、迁移、炎症和损伤中的作用。结果表明，Stig在CHON-001软骨细胞中未表现出明显的细胞毒性。有趣的是，它有效抑制LPS诱导的细胞凋亡，并提高细胞活力、增殖和迁移能力。Stig还减轻了LPS诱导的促炎反应和CHON-001细胞损伤。机制上，Stig激活核因子红细胞2相关因子2（Nrf2）信号通路，导致NOD样受体蛋白3（NLRP3）炎性小体失活，随后CHON-001细胞焦亡减少。然而，Stig的保护作用被Nrf2的特异性抑制剂ML385消除。Stig治疗进一步改善了RA小鼠的临床严重程度。总之，Stig通过抑制Nrf2/NLRP3介导的焦亡减少LPS诱导的软骨细胞损伤并减轻RA进展，为RA提供了一种潜在的治疗方法。
