Department of Orthopedics, First Hospital of China Medical University, Shenyang, China.
Department of Sports Medicine and Joint Surgury/Orthopedics, First Hospital of China Medical University, No.155 Nanjing North Street, Shenyang, China.
Sci Rep. 2024 Aug 27;14(1):19877. doi: 10.1038/s41598-024-70991-6.
Osteoarthritis (OA) is a common joint disease associated with the aging of the population, and it reduces the quality of life of patients. It is characterized by the destruction of articular cartilage and the secretion of inflammatory cytokines. Owing to the unclear pathogenesis of OA, current treatment methods have significant limitations. Oxidative stress has been revealed to play an important role in the development of OA. Our experiments indicated that the levels of GSH decreased and the level of MDA increased in chondrocytes, which induced ferroptosis in chondrocytes in OA. We also revealed that ferroptosis was the main mechanism of cartilage destruction caused by the addition of the ferroptosis activator erastin and the ferroptosis inhibitor ferrostatin-1. NOX1 is the main modulator of oxidative stress by increasing the generation of reactive oxidative species (ROS). We suppressed the expression of NOX1 in chondrocytes through cell transfection. The expression of collagen II and MMP13, and the secretion of IL-1β and TNF-α were reversed. An increase in the mitochondrial membrane potential and a decrease in the level of intracellular ROS indicate an improvement in oxidative damage. Additionally, we determined the effect of the Nrf2/HO-1 pathway on NOX1-mediated chondrocyte injury. We found that NOX1 inhibited the expression of Nrf2/HO-1, but the activation of Nrf2 improved the oxidative damage to chondrocytes in vivo and vitro. This study revealed that NOX1-mediated oxidative stress induces chondrocyte ferroptosis by inhibiting the Nrf2/HO-1 pathway. Our findings contribute to revealing the pathogenesis of OA, providing targets for drug design and optimizing the clinical treatment of OA.
骨关节炎（OA）是一种与人口老龄化相关的常见关节疾病，它降低了患者的生活质量。其特征为关节软骨破坏和炎症细胞因子的分泌。由于 OA 的发病机制尚不清楚，目前的治疗方法存在很大的局限性。氧化应激被发现在 OA 的发展中起着重要作用。我们的实验表明，OA 软骨细胞中的 GSH 水平降低，MDA 水平升高，诱导软骨细胞发生铁死亡。我们还揭示了铁死亡是铁死亡激活剂 erastin 和铁死亡抑制剂 ferrostatin-1 引起软骨破坏的主要机制。NOX1 通过增加活性氧（ROS）的产生来调节氧化应激。我们通过细胞转染抑制软骨细胞中 NOX1 的表达，逆转了胶原 II 和 MMP13 的表达，以及 IL-1β和 TNF-α的分泌。线粒体膜电位的增加和细胞内 ROS 水平的降低表明氧化损伤得到改善。此外，我们还确定了 Nrf2/HO-1 通路对 NOX1 介导的软骨细胞损伤的影响。我们发现，NOX1 抑制了 Nrf2/HO-1 的表达，但 Nrf2 的激活改善了体内和体外软骨细胞的氧化损伤。这项研究揭示了 NOX1 介导的氧化应激通过抑制 Nrf2/HO-1 通路诱导软骨细胞铁死亡。我们的研究结果有助于揭示 OA 的发病机制，为药物设计提供靶点，并优化 OA 的临床治疗。
