Kim Yu Jung, Han Jin, Han Seungwoo
Laboratory for Arthritis and Cartilage Biology, Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Cartilage. 2024 Apr 20:19476035241245803. doi: 10.1177/19476035241245803.
Oxidative stress and endoplasmic reticulum (ER) stress play pivotal roles in disrupting the homeostasis of chondrocytes by producing catalytic proteases and enhancing chondrocyte senescence, consequently contributing to the progression of osteoarthritis (OA). Despite their close interaction, the underlying molecular mechanisms remain poorly understood. Here, we show that ER stress and oxidative stress reciprocally modulate each other to promote cartilage degradation.
Primary chondrocytes were obtained from the articular cartilage of 5-day-old C57BL/6J mice by excising distal femur and proximal tibia. Tunicamycin was applied to induce ER stress in primary chondrocytes. Surgical OA was induced in 12-week-old male C57BL/6J mice by destabilizing the medial meniscus (DMM).
Tunicamycin-induced ER stress led to an increase in the production of reactive oxygen species (ROS) and catalytic proteases, including MMP13 and Adamts5, in primary chondrocytes, and it was primarily dependent on the NADPH oxidase (NOX) system. ER stress directly increased the expression of NOX2, NOX3, NOX4, and p22phox. Specifically, the protein kinase RNA-like ER kinase (PERK) pathway is involved in the expression of NOX4 and p22phox, the inositol-requiring enzyme 1 alpha (IRE1α) pathway in NOX2 and NOX3 expression, and the activating transcription factor 6 (ATF6) pathway influences NOX3 expression in chondrocytes. Conversely, inhibiting NOX function significantly reduced both ER stress sensor-related signaling and chondrocyte catabolism, thereby decelerating the progression of surgically induced OA .
Our findings highlight the positive feedback loop between ER stress and oxidative stress in OA pathogenesis, suggesting that targeting NOX isoforms is a promising therapeutic strategy for OA.
氧化应激和内质网（ER）应激通过产生催化蛋白酶和促进软骨细胞衰老，在破坏软骨细胞内稳态中起关键作用，从而推动骨关节炎（OA）的进展。尽管它们密切相互作用，但其潜在分子机制仍知之甚少。在此，我们表明内质网应激和氧化应激相互调节以促进软骨降解。
通过切除5日龄C57BL/6J小鼠的股骨远端和胫骨近端，从其关节软骨中获取原代软骨细胞。用衣霉素诱导原代软骨细胞发生内质网应激。通过使内侧半月板不稳定（DMM）在12周龄雄性C57BL/6J小鼠中诱导手术性骨关节炎。
衣霉素诱导的内质网应激导致原代软骨细胞中活性氧（ROS）和催化蛋白酶（包括MMP13和Adamts5）的产生增加，且主要依赖于NADPH氧化酶（NOX）系统。内质网应激直接增加了NOX2、NOX3、NOX4和p22phox的表达。具体而言，蛋白激酶RNA样内质网激酶（PERK）途径参与NOX4和p22phox的表达，肌醇需求酶1α（IRE1α）途径参与NOX2和NOX3的表达，而激活转录因子6（ATF6）途径影响软骨细胞中NOX3的表达。相反，抑制NOX功能显著降低了内质网应激传感器相关信号传导和软骨细胞分解代谢，从而减缓了手术诱导的骨关节炎的进展。
我们的研究结果突出了骨关节炎发病机制中内质网应激和氧化应激之间的正反馈回路，表明靶向NOX亚型是一种有前景的骨关节炎治疗策略。
