Fig. 4

Illustration of the ER stress response and its implications in OA. The diagram depicts the activation of the UPR due to the accumulation of misfolded proteins within the ER. Key ER stress sensors, including PERK, IRE1α, and ATF6α, are activated upon dissociation from the chaperone BiP. PERK phosphorylates eIF2α to attenuate protein synthesis, whereas IRE1α splices XBP1 mRNA to generate the active transcription factor XBP1s, which promotes the expression of chaperones and proteins involved in ER expansion. Upon cleavage, ATF6α translocates to the nucleus to activate UPR target genes that aid in protein folding and ER homeostasis. The figure also highlights the role of hypoxia, mutated collagen II, and AGEs in promoting ER stress. Prolonged ER stress can lead to the activation of proapoptotic pathways, including the CHOP pathway, and the production of matrix-degrading enzymes such as MMPs and ADAMTSs, contributing to cartilage degradation in OA. UPR unfolded protein response, PERK protein kinase-RNA-like endoplasmic reticulum kinase, IRE1α inositol-requiring enzyme 1 alpha, ATF6α activating transcription factor 6α, BiP glucose-regulated protein 78, eIF2α eukaryotic translation initiation factor 2A, ATF4 activating transcription factor 4, CHOP C/EBP homologous protein, XBP1 X-box binding protein 1, XBP1s spliced X-box binding protein 1, TRAF2 TNFR-associated factor 2, AGEs advanced glycation end products