Inflammation and loss of articular cartilage are considered the major cause of temporomandibular joint osteoarthritis (TMJOA), a painful condition of the temporomandibular joint (TMJ). To determine the cause of TMJ osteoarthritis in these patients, synovial fluid of TMJOA patients was compared prior to and after hyaluronic lavage, revealing substantially elevated levels of interleukin (IL) 1β, reactive oxidative stress (ROS), and an overload of Fe3+ and Fe2+ prior to lavage, indicative of ferroptosis as a mode of chondrocyte cell death. To ask whether prolonged inflammatory conditions resulted in ferroptosis-like transformation in vitro, we subjected TMJ chondrocytes to IL-1β treatment, resulting in a shift in messenger RNA sequencing gene ontologies related to iron homeostasis and oxidative stress–related cell death. Exposure to rat unilateral anterior crossbite conditions resulted in reduced COL2A1 expression, fewer chondrocytes, glutathione peroxidase 4 (GPX4) downregulation, and 4-hydroxynonenal (4-HNE) upregulation, an effect that was reversed after intra-articular injections of the ferroptosis inhibitor ferrostatin 1 (Fer-1). Our study demonstrated that ferroptosis conditions affected mitochondrial structure and function, while the inhibitor Fer-1 restored mitochondrial structure and the inhibition of hypoxia-inducible factor 1α (HIF-1α) or the transferrin receptor 1 (TFRC) rescued IL-1β–induced loss of mitochondrial membrane potential. Inhibition of HIF-1α downregulated IL-1β–induced TFRC expression, while inhibition of TFRC did not downregulate IL-1β–induced HIF-1α expression in chondrocytes. Moreover, inhibition of HIF-1α or TFRC downregulated the IL-1β–induced MMP13 expression in chondrocytes, while inhibition of HIF-1α or TFRC rescued IL-1β–inhibited COL2A1 expression in chondrocytes. Furthermore, upregulation of TFRC promoted Fe2+ entry into chondrocytes, inducing the Fenton reaction and lipid peroxidation, which in turn caused ferroptosis, a disruption in chondrocyte functions, and an exacerbation of condylar cartilage degeneration. Together, these findings illustrate the far-reaching effects of chondrocyte ferroptosis in TMJOA as a mechanism causing chondrocyte death through iron overload, oxidative stress, and articular cartilage degeneration and a potential major cause of TMJOA.

中文翻译：

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炎症通过 HIF-1α/TFRC 触发 TMJOA 软骨细胞铁死亡


关节软骨的炎症和损失被认为是颞下颌关节骨关节炎（TMJOA）的主要原因，颞下颌关节骨关节炎是颞下颌关节（TMJ）的一种疼痛性疾病。为了确定这些患者 TMJ 骨关节炎的原因，对 TMJOA 患者在透明质酸灌洗前后的滑液进行了比较，结果显示白细胞介素 (IL) 1β、反应性氧化应激 (ROS) 以及 Fe3+ 和 Fe2+ 超载水平显着升高灌洗前，表明铁死亡是软骨细胞死亡的一种模式。为了探究长期炎症条件是否会导致体外铁死亡样转化，我们对 TMJ 软骨细胞进行 IL-1β 处理，导致与铁稳态和氧化应激相关细胞死亡相关的信使 RNA 测序基因本体发生变化。暴露于大鼠单侧前牙反牙合条件下，导致 COL2A1 表达减少、软骨细胞减少、谷胱甘肽过氧化物酶 4 (GPX4) 下调和 4-羟基壬烯醛 (4-HNE) 上调，这种效应在关节内注射铁死亡抑制剂铁他汀后逆转1（Fer-1）。我们的研究表明，铁死亡条件影响线粒体结构和功能，而抑制剂 Fer-1 可以恢复线粒体结构，并且抑制缺氧诱导因子 1α (HIF-1α) 或转铁蛋白受体 1 (TFRC) 可以挽救 IL-1β 诱导的线粒体损失线粒体膜电位。抑制 HIF-1α 会下调 IL-1β 诱导的 TFRC 表达，而抑制 TFRC 不会下调软骨细胞中 IL-1β 诱导的 HIF-1α 表达。 此外，抑制 HIF-1α 或 TFRC 下调了软骨细胞中 IL-1β 诱导的 MMP13 表达，而抑制 HIF-1α 或 TFRC 则挽救了软骨细胞中 IL-1β 抑制的 COL2A1 表达。此外，TFRC的上调促进Fe2+进入软骨细胞，诱导芬顿反应和脂质过氧化，进而导致铁死亡、软骨细胞功能破坏和髁软骨退化加剧。总之，这些发现说明了软骨细胞铁死亡对 TMJOA 的深远影响，它是通过铁超载、氧化应激和关节软骨变性导致软骨细胞死亡的机制，也是 TMJOA 的潜在主要原因。