4-octyl Itaconate inhibits lipopolysaccharide (LPS)-induced osteoarthritis via activating Nrf2 signalling pathway.
4-octyl Itaconate inhibits lipopolysaccharide (LPS)-induced osteoarthritis via activating Nrf2 signalling pathway.
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DOI：
10.1111/jcmm.17185
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发表时间：
2022-03
影响因子：
5.3
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Zhang Q;Bai X;Wang R;Zhao H;Wang L;Liu J;Li M;Chen Z;Wang Z;Li L;Wang D
对软骨细胞的小分子药物干预是治疗骨关节炎 (OA) 的一种有价值的方法。衣康酸 4-辛酯 (OI) 是衣康酸的细胞衍生物，具有良好的细胞渗透性和转化率。我们试图证实OI对软骨细胞的保护作用及其调节机制。我们使用脂多糖（LPS）来诱导软骨细胞炎症损伤。 OI治疗后，通过ELISA和qPCR检测Il-6、Il-10、Mcp-1和Tnf-α的分泌和mRNA表达。 OI对关节软骨的保护作用在OA内侧半月板模型的手术失稳中得到进一步验证。基于 CCK8、LDH、台盼蓝染色、膜联蛋白 V 和 TUNEL 分析评估细胞死亡和凋亡。小干扰 RNA 用于敲除软骨细胞的 Nrf2 基因，以验证 OI 介导的 Nrf2 信号通路。结果表明，OI 可以保护细胞免受 LPS 诱导的炎症损伤，并减轻 LPS 诱导的细胞死亡和凋亡。对小鼠关节软骨也观察到类似的保护作用。 OI 激活 Nrf2 信号通路并促进 Nrf2 的稳定表达和转位到细胞核中。当 Nrf2 信号通路被阻断时，成骨不全的保护作用在软骨细胞和小鼠关节炎模型中显着抵消。衣康酸及其衍生物（即 OI）在治疗 OA 方面显示出重要的医疗作用。
Small molecule drug intervention for chondrocytes is a valuable method for the treatment of osteoarthritis (OA). The 4‐octyl itaconate (OI) is a cellular derivative of itaconate with sound cell permeability and transformation rate. We attempted to confirm the protective role of OI in chondrocytes and its regulatory mechanism. We used lipopolysaccharide (LPS) to induce chondrocyte inflammation injury. After the OI treatment, the secretion and mRNA expression of Il‐6, Il‐10, Mcp‐1 and Tnf‐α were detected by ELISA and qPCR. The protective effect of OI on articular cartilage was further verified in surgical destabilization of the medial meniscus model of OA. Cell death and apoptosis were evaluated based on CCK8, LDH, Typan blue staining, Annexin V and TUNEL analyses. The small interfering RNAs were used to knockout the Nrf2 gene of chondrocytes to verify the OI‐mediated Nrf2 signalling pathway. The results revealed that OI protects cells from LPS‐induced inflammatory injury and attenuates cell death and apoptosis induced by LPS. Similar protective effects were also observed on articular cartilage in mice. The OI activated Nrf2 signalling pathway and promoted the stable expression and translocation of Nrf2 into the nucleus. When the Nrf2 signalling pathway was blocked, the protective effect of OI was significantly counteracted in chondrocytes and a mouse arthritis model. Both itaconate and its derivative (i.e., OI) showed important medical effects in the treatment of OA.
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