LncRNA HOXC-AS3 prevents chondrocyte senescence and osteoarthritis progression through miR-615-3p sponging and RRBP1...

Osteoarthritis (OA) is a widespread chronic joint disorder characterized by progressive cartilage degeneration, leading to substantial impairment in quality of life for millions of individuals globally. Cellular senescence has been increasingly recognized as a central contributor to OA pathogenesis, with senescent chondrocytes exhibiting a senescence-associated secretory phenotype that promotes tissue destruction. Long non-coding RNAs (lncRNAs) are known to play essential roles in maintaining cartilage homeostasis; however, their regulatory functions in OA remain poorly defined. This study aimed to elucidate the expression patterns, biological roles, and molecular mechanisms of lncRNA HOXC-AS3 in chondrocyte physiology and OA development.

HOXC-AS3 expression was markedly reduced in OA-affected cartilage tissues and in human chondrocytes exposed to IL-1β. Functional analyses revealed that HOXC-AS3 knockdown suppressed chondrocyte proliferation, accelerated cellular senescence, and disrupted extracellular matrix homeostasis, whereas its overexpression ameliorated IL-1β-induced chondrocyte dysfunction. Mechanistically, HOXC-AS3 operates through two distinct pathways: acting as a competing endogenous RNA by directly sequestering miR-615-3p, and physically interacting with ribosome-binding protein 1 (RRBP1). Both pathways converge to regulate the expression of citron rho-interacting serine/threonine kinase (CIT), a critical modulator of the cell cycle. Notably, CIT knockdown mimicked the phenotypic effects of HOXC-AS3 deficiency, while HOXC-AS3 overexpression preserved chondrocyte function by sustaining CIT expression under inflammatory stress.

This study establishes lncRNA HOXC-AS3 as a key regulator of chondrocyte homeostasis that mitigates OA progression via dual mechanisms-miR-615-3p sponging and RRBP1 interaction-both of which maintain CIT expression. These findings advance the understanding of the molecular networks underlying OA pathogenesis and underscore HOXC-AS3 and its downstream signaling axis as promising therapeutic targets for OA intervention.