炎症通过 HIF-1α/TFRC 触发颞下颌关节畸形中的软骨细胞铁凋亡

Journal of dental research Pub Date : 2024-07-01 Epub Date: 2024-05-20 DOI:10.1177/00220345241242389
B Y Chen, J L Pathak, H Y Lin, W Q Guo, W J Chen, G Luo, L J Wang, X F Sun, Y Ding, J Li, T G H Diekwisch, C Liu
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引用次数: 0

摘要

颞下颌关节骨关节炎(TMJOA)是颞下颌关节(TMJ)的一种疼痛性疾病,炎症和关节软骨损失被认为是其主要原因。为了确定这些患者颞下颌关节骨关节炎的病因,我们比较了透明质酸灌洗前后颞下颌关节骨关节炎患者滑膜液的情况,结果发现白细胞介素(IL)1β、反应性氧化应激(ROS)水平大幅升高,灌洗前Fe3+和Fe2+超负荷,这表明软骨细胞死亡的一种模式是铁变态反应。为了探究长期的炎症条件是否会导致体外的类铁变态反应,我们让颞下颌关节软骨细胞接受IL-1β处理,结果发现与铁平衡和氧化应激相关的细胞死亡有关的信使RNA测序基因本体发生了变化。在大鼠单侧前交叉咬合条件下,COL2A1表达减少,软骨细胞减少,谷胱甘肽过氧化物酶4(GPX4)下调,4-羟基壬烯醛(4-HNE)上调。我们的研究表明,铁变态反应会影响线粒体的结构和功能,而抑制剂 Fer-1 可恢复线粒体结构,抑制缺氧诱导因子 1α(HIF-1α)或转铁蛋白受体 1(TFRC)可挽救 IL-1β 诱导的线粒体膜电位损失。抑制 HIF-1α 会下调 IL-1β 诱导的 TFRC 表达,而抑制 TFRC 不会下调 IL-1β 诱导的 HIF-1α 在软骨细胞中的表达。此外,抑制 HIF-1α 或 TFRC 可下调 IL-1β 诱导的 MMP13 在软骨细胞中的表达,而抑制 HIF-1α 或 TFRC 可挽救 IL-1β 抑制的 COL2A1 在软骨细胞中的表达。此外,TFRC 的上调会促进 Fe2+ 进入软骨细胞,诱导 Fenton 反应和脂质过氧化反应,进而引起铁变态反应、软骨细胞功能紊乱和髁状软骨退化加剧。这些发现共同说明了软骨细胞铁变态反应在 TMJOA 中的深远影响,它是一种通过铁超载、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 的潜在主要病因。
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Inflammation Triggers Chondrocyte Ferroptosis in TMJOA via HIF-1α/TFRC.

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.

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