In cartilage, chondrocytes are responsible for the biogenesis and maintenance of the extracellular matrix (ECM) composed of proteins, glycoproteins and proteoglycans. Various cellular stresses, such as hypoxia, nutrient deprivation, oxidative stress or the accumulation of advanced glycation end products (AGEs) during aging, but also translational errors or mutations in cartilage components or chaperone proteins affect the synthesis and secretion of ECM proteins, causing protein aggregates to accumulate in the endoplasmic reticulum (ER). This condition, referred to as ER stress, interferes with cartilage cell homeostasis and initiates the unfolded protein response (UPR), a rescue mechanism to regain cell viability and function. Chronic or irreversible ER stress, however, triggers UPR-initiated cell death. Due to unresolved ER stress in chondrocytes, diseases of the skeletal system, such as chondrodysplasias, arise. ER stress has also been identified as a contributing factor to the pathogenesis of cartilage degeneration processes such as osteoarthritis (OA). This review provides current knowledge about the biogenesis of ECM components in chondrocytes, describes possible causes for the impairment of involved processes and focuses on the ER stress-induced cell death in articular cartilage during OA. Targeting of the ER stress itself or intervention in UPR signaling to reduce death of chondrocytes may be promising for future osteoarthritis therapy.

在软骨中，软骨细胞负责由蛋白质、糖蛋白和蛋白聚糖组成的细胞外基质 (ECM) 的生物发生和维持。各种细胞应激，如缺氧、营养缺乏、氧化应激或衰老过程中晚期糖基化终产物 (AGEs) 的积累，以及软骨成分或伴侣蛋白的翻译错误或突变都会影响 ECM 蛋白的合成和分泌，导致蛋白质聚集体在内质网 (ER) 中积累。这种情况称为内质网应激，会干扰软骨细胞稳态并启动未折叠蛋白反应 (UPR)，这是一种恢复细胞活力和功能的拯救机制。然而，慢性或不可逆的内质网应激会触发 UPR 引发的细胞死亡。由于软骨细胞中未解决的内质网应激，出现骨骼系统疾病，例如软骨发育不良。内质网应激也被确定为软骨退化过程（如骨关节炎 (OA)）发病机制的一个促成因素。本综述提供了有关软骨细胞中 ECM 成分生物发生的最新知识，描述了相关过程受损的可能原因，并重点关注 OA 期间内质网应激诱导的关节软骨细胞死亡。针对 ER 应激本身或干预 UPR 信号以减少软骨细胞的死亡可能有希望用于未来的骨关节炎治疗。本综述提供了有关软骨细胞中 ECM 成分生物发生的最新知识，描述了相关过程受损的可能原因，并重点关注 OA 期间内质网应激诱导的关节软骨细胞死亡。针对 ER 应激本身或干预 UPR 信号以减少软骨细胞的死亡可能有希望用于未来的骨关节炎治疗。本综述提供了有关软骨细胞中 ECM 成分生物发生的最新知识，描述了相关过程受损的可能原因，并重点关注 OA 期间内质网应激诱导的关节软骨细胞死亡。针对 ER 应激本身或干预 UPR 信号以减少软骨细胞的死亡可能有希望用于未来的骨关节炎治疗。