骨关节炎中的线粒体内质网应激串扰：从衰老相关的软骨细胞功能障碍到新兴疗法

摘要(中文译文)

骨关节炎（OA）是一种常见的与年龄相关的关节疾病，其驱动因素不仅包括机械磨损，还涉及进行性细胞内应激、代谢失衡和慢性炎症，最终导致软骨退变和功能障碍。越来越多的证据表明，线粒体功能障碍和内质网应激（ERS）是调控软骨细胞存活、细胞外基质（ECM）完整性和炎症信号传导的核心病理枢纽。线粒体损伤促进活性氧（ROS）过度生成、ATP产生缺陷、线粒体动力学紊乱以及线粒体自噬不足，共同加速ECM分解代谢和软骨细胞凋亡。与此同时，ERS激活未折叠蛋白反应（UPR），通过PERK、IRE1α和ATF6通路恢复蛋白质稳态；然而，持续的UPR激活从适应性信号转变为适应不良性结局，放大OA软骨中的炎症、氧化损伤和细胞死亡。值得注意的是，新近数据突显了线粒体与内质网之间的双向交互作用，尤其是通过线粒体相关膜（MAMs），作为Ca²⁺调控异常、炎症小体激活和退变性关节重塑的关键驱动因素。针对这些应激通路的治疗策略，包括线粒体抗氧化剂、NAD⁺增强剂、线粒体自噬调节剂、化学 chaperone 和选择性UPR调节剂，已显示出减轻软骨破坏和恢复关节稳态的潜力。本综述综合了目前关于OA中线粒体-ERS信号传导机制的认识，并批判性评估了旨在重编程细胞内应激的不断发展的疾病修饰干预措施。最后，我们讨论了利用细胞器应激通路开发精准疗法以改善长期关节健康的转化挑战和未来方向。

Abstract

Osteoarthritis (OA) is a common age-associated joint disorder driven not only by mechanical wear but also by progressive intracellular stress, metabolic imbalance, and chronic inflammation that culminate in cartilage degeneration and functional disability. Increasing evidence identifies mitochondrial dysfunction and endoplasmic reticulum stress (ERS) as central pathological hubs regulating chondrocyte survival, extracellular matrix (ECM) integrity, and inflammatory signaling. Mitochondrial impairment promotes excessive reactive oxygen species (ROS) generation, defective ATP production, disturbed mitochondrial dynamics, and inadequate mitophagy, collectively accelerating ECM catabolism and chondrocyte apoptosis. In parallel, ERS activates the unfolded protein response (UPR) to restore proteostasis through the PERK, IRE1α, and ATF6 pathways; however, sustained UPR activation shifts from adaptive signaling to maladaptive outcomes, amplifying inflammation, oxidative injury, and cell death in OA cartilage. Notably, emerging data highlight bidirectional crosstalk between mitochondria and ER, particularly via mitochondria-associated membranes (MAMs), as a key driver of Ca²⁺ dysregulation, inflammasome activation, and degenerative joint remodeling. Therapeutic strategies targeting these stress pathways including mitochondrial antioxidants, NAD⁺-boosting agents, mitophagy modulators, chemical chaperones, and selective UPR regulators have demonstrated potential to attenuate cartilage destruction and restore joint homeostasis. This review synthesizes current mechanistic insights into mitochondrial ERS signaling in OA and critically evaluates evolving disease-modifying interventions aimed at intracellular stress reprogramming. Finally, we discuss translational challenges and future directions for developing precision therapies that exploit organelle stress pathways to improve long-term joint health.

如何引用

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