Novel snoRNA-derived fragment sdRNA-D21 enhances ER stress-induced chondrocyte apoptosis in osteoarthritis by targeting BAG2-mediated ER-phagy and DEPTOR

This study aimed to explore the role of sdRNA-D21, a novel small nucleolar RNA-derived fragment (sdRNA), in osteoarthritis (OA). Two sdRNA-sequencing analyses of cartilage and chondrocytes from OA patients were performed to investigate the potential association between sdRNAs and OA. Quantitative real-time PCR and fluorescence in situ hybridization were used to determine the expression levels of sdRNA-D21. sdRNA-D21 mimic and inhibitor of sdRNA-D21 were used for the gain- and loss-of-function experiments. Bioinformatics analysis, luciferase reporter assays, RNA pulldown assays, RNA immunoprecipitation, co-immunoprecipitation, transmission electron microscopy and fluorescence co-localization shed light on the regulatory role of sdRNA-D21 in OA. DMM-induced OA rat model was used for the in vivo study. sdRNA-D21 was overexpressed in OA cartilage, with expression levels clinically correlating with knee OA severity. Functionally, sdRNA-D21 knockdown alleviated OA development both in vitro and in vivo. Mechanistically, sdRNA-D21 induced chondrocyte apoptosis through (1) impairing ER-phagy by targeting BAG2 and thereby blocking p62 recruitment, and (2) enhancing TRC8-mediated ER stress by silencing DEPTOR expression. Collectively, the findings of this study identify sdRNA-D21 as a novel driver of OA progression and a potential molecular target for OA intervention, providing a foundational theoretical basis for the subsequent development of targeted therapeutic strategies against OA.