Sel1l preserves condylar cartilage matrix homeostasis by regulating PERK signaling

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease with orofacial pain and impaired joint function. However, the mechanisms are not well understood. Sel1l‐mediated endoplasmic reticulum‐associated degradation (ERAD) orchestrates protein homeostasis. Here, we investigated the roles and mechanisms of Sel1l‐mediated ERAD in TMJOA induced by complete Freund's adjuvant injection and disc displacement. The osteoarthritic cartilage presented dysregulated ERAD signaling, and the expression of Sel1l was decreased in early OA condition. Intra‐articular injection of sh‐Sel1l adeno‐associated virus induced cartilage catabolism. The RNA‐sequencing data and immunofluorescence staining also showed the upregulation of genes related to extracellular matrix (ECM) degradation, while the downregulation of genes associated with chondrogenic differentiation in Sel1l‐depleted chondrocytes. These results indicate that Sel1l deficiency induced cartilage catabolism both in vivo and in vitro. Mechanistically, Sel1l‐depleted chondrocytes were revealed to harbor excessive endoplasmic reticulum (ER) stress, especially mediated by PERK activation. PERK inhibition suppressed the expression of ER stress markers, rescued the ECM degradation of Sel1l‐depleted condylar chondrocytes, and relieved the TMJOA pathogenesis.