LncRNA HOXC-AS3 Prevents Chondrocyte Senescence and Osteoarthritis Progression Through miR-615-3p Sponging and RRBP1 Interaction

Background: Osteoarthritis (OA) is a prevalent chronic joint disease characterized by progressive cartilage degeneration, significantly impairing quality of life for millions worldwide. Cellular senescence has emerged as a pivotal driver of OA pathogenesis, with senescent chondrocytes exhibiting a senescence-associated secretory phenotype that exacerbates tissue degradation. Long non-coding RNAs (lncRNAs) play critical roles in cartilage homeostasis, yet their regulatory mechanisms in OA remain incompletely understood. This study aimed to investigate the expression patterns, biological functions, and underlying mechanisms of lncRNA HOXC-AS3 in chondrocyte biology and OA pathogenesis. Results: LncRNA HOXC-AS3 was significantly downregulated in both OA cartilage tissues and IL-1β-treated human chondrocytes. Functional experiments demonstrated that HOXC-AS3 knockdown inhibited chondrocyte proliferation, promoted cellular senescence, and caused extracellular matrix imbalance, while its overexpression effectively reversed IL-1β-induced chondrocyte dysfunction. Mechanistic investigations revealed that HOXC-AS3 functions through dual molecular mechanisms: serving as a competing endogenous RNA by directly binding to miR-615-3p, and interacting with ribosome-binding protein 1 (RRBP1). Both mechanisms converged to regulate the expression of citron rho-interacting serine/threonine kinase (CIT), a key cell cycle regulator. Notably, CIT knockdown recapitulated the cellular phenotypes observed with HOXC-AS3 deficiency, while HOXC-AS3 overexpression rescued chondrocyte function by maintaining CIT expression levels even under inflammatory conditions. Conclusions: Our study identifies lncRNA HOXC-AS3 as a critical regulator of chondrocyte homeostasis that protects against OA progression through novel dual mechanisms: miR-615-3p sponging and RRBP1 interaction, both converging to maintain CIT expression. These findings not only enhance our understanding of the complex regulatory networks underlying OA pathogenesis but also highlight HOXCAS3 and its downstream effectors as potential therapeutic targets for OA treatment.