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BACKGROUND Osteoarthritis (OA) is the predominant threaten to the health of the elderly, and it is crucial to understand the molecular pathegenetic mechanisms involved in it. This study aims to investigate the role of a well-studied cancer-related long noncoding RNA (lncRNA)-POU3F3 in OA and its implicated molecular mechanisms. METHOD The expression of POU3F3 and miR-29a-3p was examined in osteoarthritis patients, destabilization of the medial meniscus (DMM) mouse OA model, and IL- 1β induced chondrocytes cell OA model by quantitative real-time PCR. The interaction between POU3F3, miR-29a-3p and transcription factor forkhead box O3 (FOXO3) was verified by via dual-luciferase reporter analysis and RNA immunoprecipitation analyses. Cell proliferation and apoptosis were evaluated by cell viability assay and flow cytometry, respectively. Cartilage extracellular matrix (ECM) degradation were investigated with ELISA and western blotting. In addition, the in vivo regulation of POU3F3 in OA was verified by intra-articular injection of lentivirus overexpression POU3F31 in mice models. RESULTS The expression level of POU3F3 was decreased in OA patients/animal cartilage tissues and IL-1β-stimulated in vitro chondrocyte model. POU3F3 overexpression inhibited IL-1β-induced injury of chondrocytes, enhancing cell viability, suppressing apoptosis and inflammatory cytokine secretion, rescuing metabolic dysfunction, and restrained autophagy in vitro. Mechanistically, Luciferase reporter and RNA immunoprecipitation (RIP) assays indicated that miR-29a-3p could directly bind to POU3F3 and FOXO3 was a target gene of miR-29a-3p. Functional rescue assays confirmed this POU3F3/miR-29a-3p/FOXO3 axis in chondrocytes during OA occurrence. Furthermore, intra-articularly delivery of lentivirus containing POU3F3 alleviates the damage in mouse OA model in vivo. CONCLUSION In conclusion, this work highlights the function of POU3F3/miR-29a-3p/FOXO3 axis in OA pathogenesis, suggesting this axis as a potential progression of OA [12-15]. These studies indicate the potential contribution of lncRNAs in the development of OA and a promising target for disease diagnosis and treatment.