Stage-specific miRNA signatures in osteoarthritis identify miR-4505 and miR-331-3p as key modulators of disease pathogenesis via ERBB2 suppression.

Osteoarthritis (OA) is a progressive degenerative joint disease and a leading cause of disability in the elderly, yet reliable biomarkers for early diagnosis and therapeutic intervention remain limited. Circulating miRNAs have emerged as stable, non-invasive candidates with diagnostic and regulatory potential. In this study, genome-wide microarray profiling of synovial fluid from early- and late-stage OA patients (n = 10) identified differentially expressed miRNAs, which were further validated by qRT-PCR in an extended cohort (n = 37) using both synovial fluid and serum. Tissue-level expression was examined in paired cartilage and synovium from OA patients (n = 15) and non-OA controls (n = 15). Bioinformatic predictions and functional validation through mimic/inhibitor transfection in IL-1β-stimulated SW1353 chondrocytes were performed to elucidate downstream targets and pathways. Seven miRNAs were found to be downregulated in late-stage OA, with miR-4505 and miR-331-3p consistently decreased across synovial fluid, serum, cartilage, and synovium. Serum levels of these miRNAs were independent of age, and miR-331-3p demonstrated strong discriminative ability (AUC = 0.81). ERBB2 was identified as a common downstream target, and overexpression of miR-4505 or miR-331-3p was associated with reduced ERBB2 expression, accompanied by attenuation of catabolic gene expression and inflammatory responses in vitro. These findings suggest that stage-specific downregulation of miR-4505 and miR-331-3p may reflect their involvement in OA pathogenesis. Beyond their potential utility as biomarkers, their ability to influence ERBB2-associated signaling pathways highlights their relevance as candidates for further translational investigation in OA.