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Interplay between lipid dysregulation and ferroptosis in chondrocytes and the targeted therapy effect of metformin on osteoarthritis
Journal of Advanced Research ( IF 10.7 ) Pub Date : 2024-04-14 , DOI: 10.1016/j.jare.2024.04.012
Zhi Zou , Wenhui Hu , Fei Kang , Zhonghua Xu , Yuheng Li , Jing Zhang , Jianmei Li , Yuan Zhang , Shiwu Dong

Osteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide; the role of lipid dysregulation in OA and mechanisms underlying targeted therapy effect of lipid-lowering metformin on OA remains poorly defined. To investigate the effects of lipid dysregulation on OA progression and to explore lipid dysregulation-targeting OA treatment of metformin. RNA-Seq data, biochemical, and histochemical assays in human and murine OA cartilage as well as primary chondrocytes were utilized to determine lipid dysregulation. Effects of metformin, a potent lipid-lowering medication, on ACSL4 expression and chondrocyte metabolism were determined. Further molecular experiments, including RT-qPCR, western blotting, flow cytometry, and immunofluorescence staining, were performed to investigate underlying mechanisms. Mice with intra-articular injection of metformin were utilized to determine the effects on ACLT-induced OA progression. ACSL4 and 4-HNE expressions were elevated in human and ACLT-induced mouse OA cartilage and IL-1β-treated chondrocytes ( < 0.05). Ferrostatin-1 largely rescued IL-1β-induced MDA, lipid peroxidation, and ferroptotic mitochondrial morphology ( < 0.05). Metformin decreased the levels of OA-related genes ( < 0.05) and increased the levels of p-AMPK and p-ACC in IL-1β-treated chondrocytes. Intra-articular injection of metformin alleviated ACLT-induced OA lesions in mice, and reverted the percentage of chondrocytes positive for MMP13, Col2a1, ACSL4 and 4-HNE in ACLT mice ( < 0.05). Ferroptotic chondrocytes promoted the recruitment and chemotaxis of RAW264.7 cells via CCL2, which was blocked by metformin ( < 0.05). We establish a critical role of polyunsaturated fatty acids metabolic process in OA cartilage degradation and define metformin as a potential OA treatment. Metformin reshapes lipid availability and ameliorates chondrocyte ferroptosis sensitivity via the AMPK/ACC pathway. In the future, gene-edited animals and extensive omics technologies will be utilized to reveal detailed lipids’ involvement in cartilage lesions.

中文翻译:

软骨细胞脂质失调与铁死亡的相互作用及二甲双胍对骨关节炎的靶向治疗作用

骨关节炎 (OA) 是一种毁灭性的全关节疾病,影响着全世界大量人口;脂质失调在 OA 中的作用以及降脂二甲双胍对 OA 的靶向治疗作用的机制仍不清楚。探讨脂质失调对 OA 进展的影响,并探索二甲双胍针对脂质失调的 OA 治疗。利用人类和小鼠 OA 软骨以及原代软骨细胞的 RNA-Seq 数据、生化和组织化学测定来确定脂质失调。确定了二甲双胍(一种有效的降脂药物)对 ACSL4 表达和软骨细胞代谢的影响。进行了进一步的分子实验,包括 RT-qPCR、蛋白质印迹、流式细胞术和免疫荧光染色,以研究潜在的机制。利用关节内注射二甲双胍的小鼠来确定对 ACLT 诱导的 OA 进展的影响。 ACSL4 和 4-HNE 表达在人类和 ACLT 诱导的小鼠 OA 软骨以及 IL-1β 处理的软骨细胞中升高 ( < 0.05)。 Ferrostatin-1 在很大程度上挽救了 IL-1β 诱导的 MDA、脂质过氧化和铁死亡线粒体形态 (< 0.05)。二甲双胍降低了 IL-1β 处理的软骨细胞中 OA 相关基因的水平 (< 0.05),并增加了 p-AMPK 和 p-ACC 的水平。关节内注射二甲双胍减轻了 ACLT 诱导的小鼠 OA 损伤,并恢复了 ACLT 小鼠中 MMP13、Col2a1、ACSL4 和 4-HNE 阳性软骨细胞的百分比 ( < 0.05)。铁死亡软骨细胞通过 CCL2 促进 RAW264.7 细胞的募集和趋化性,而二甲双胍可阻断这种作用 (< 0.05)。我们确定了多不饱和脂肪酸代谢过程在 OA 软骨降解中的关键作用,并将二甲双胍定义为潜在的 OA 治疗方法。二甲双胍通过 AMPK/ACC 途径重塑脂质可用性并改善软骨细胞铁死亡敏感性。未来,基因编辑动物和广泛的组学技术将被用来揭示脂质与软骨损伤的详细关系。
更新日期:2024-04-14
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