酮麝香酸通过SIRT1/p38MAPK信号通路减轻ROS生成和NLRP3炎症小体激活，保护免受铁过载诱导的关节炎的损害。
Cardamonin protects against iron overload induced arthritis by attenuating ROS production and NLRP3 inflammasome activation via the SIRT1/p38MAPK signaling pathway.
发表日期：2023 Aug 23
作者：
Shaocong Li, Qi He, Baihao Chen, Jiaxu Zeng, Xiangyun Dou, Zhaofeng Pan, Jiacong Xiao, Miao Li, Fanchen Wang, Chuyi Chen, Yuewei Lin, Xintian Wang, Haibin Wang, Jianfa Chen
来源：
ARTHRITIS RESEARCH & THERAPY
摘要：
铁稳态在关节健康中起着关键作用，而铁过载可能导致软骨细胞的损伤和死亡。茴香脑（CAR）是一种存在于庐柏果实中的物质，具有抗炎和抗肿瘤活性。我们首先静脉注射铁葡萄糖酸铁（500mg/kg）以建立铁过载小鼠模型，并通过手术诱导骨关节炎。在10周后，利用微CT、Safranin-O/fast green染色、H&E染色和Prussian Blue评估了骨关节炎的程度和铁沉积情况。我们使用铵橙酸亚铁处理原代软骨细胞来评估软骨细胞的变化。通过甲苯胺蓝染色在体外鉴定软骨细胞，并通过CCK-8评估软骨细胞的存活率。通过Annexin V-FITC/PI检测法确定凋亡率。通过添加SIRT1抑制剂EX527验证了CAR的作用机制，并通过Western blot检测了SIRT1和MAPK信号通路的表达。铁过载也促进了软骨细胞凋亡，而CAR则逆转了这一过程。此外，CAR通过SIRT1-MAPK途径减少了NLRP3炎症小体的产生，而SIRT1抑制剂EX527抑制了CAR对骨关节炎的治疗作用。CAR在体内和体外均能抑制铁过载引起的软骨退化。此外，我们的研究还表明，铁过载不仅抑制II型胶原蛋白的表达，还通过催化NLRP3炎症小体的产生诱导了MMP表达。我们的结果表明，CAR通过促进SIRT1表达和抑制p38MAPK信号通路的表达来减少NLRP3炎症小体的产生，从而治疗骨关节炎。© 2023. Springer Nature Limited.
Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.© 2023. Springer Nature Limited.