Endoplasmic reticulum stress-mediated apoptosis and autophagy in osteoarthritis: from molecular mechanisms to therapeutic applications.

Abstract

Osteoarthritis (OA) is characterized primarily by the degeneration of articular cartilage, with a high prevalence and disability rate. The functional phenotype of chondrocytes, as the sole cell type within cartilage, is vital for OA progression. Due to the avascular nature of cartilage and its limited regenerative capacity, repair following injury poses significant challenges. Various cellular stressors, including hypoxia, nutrient deprivation, oxidative stress, and collagen mutations, can lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress (ERS). In response to restore ER homeostasis as well as cellular vitality and function, a series of adaptive mechanisms are triggered, including the unfolded protein response (UPR), ER-associated degradation (ERAD), and ER-phagy. Prolonged or severe ERS may exceed the adaptive capacity of cells, leading to dysregulation in apoptosis and autophagy-key pathogenic factors contributing to chondrocyte damage and OA progression. This review examines the relationship between ERS in OA chondrocytes and both apoptosis and autophagy in order to identify potential therapeutic targets and strategies for prevention and treatment of OA.