Comprehensive microRNA profiling of aging cartilage in the Dunkin-Hartley guinea pig model identifies key regulators of osteoarthritis progression

Background Osteoarthritis (OA) is the leading cause of joint disability in the elderly, particularly affecting the knee. The molecular mechanisms underlying idiopathic, age-related OA remain unclear, and current therapies are largely symptom-targeted. MicroRNAs (miRNAs) are key regulators of cartilage homeostasis and inflammation, but most in vivo models fail to recapitulate idiopathic, age-associated OA. Methods The Dunkin-Hartley guinea pig model of spontaneous OA was used to investigate aging-related miRNA dysregulation. Cartilage RNA was extracted from control, early OA, and late OA groups and profiled for 100 miRNAs using RT-qPCR arrays. Histological evaluation and OARSI scoring assessed cartilage degeneration. Dysregulated miRNAs were analyzed using a bioinformatic pipeline incorporating target prediction (TargetScan, miRTarBase, DIANA microT-CDS), protein-protein interaction (STRING), network analysis (Cytoscape), and pathway enrichment (KEGG). Functional validation was performed by transfecting SW1353 cells with miR-7-5p mimics and assessing expression of predicted target genes. Results Histological analysis and OARSI scoring confirmed progressive cartilage degeneration. RT-qPCR arrays revealed significant age-dependent downregulation of miR-130b-3p, miR-7-5p, miR-20b-5p, and miR-130b-5p, with 38 miRNAs downregulated in late OA relative to controls. Network and pathway analysis identified miR-7-5p as a central regulator of OA pathogenesis. Transfection of SW1353 cells with miR-7-5p mimics suppressed expression of predicted gene targets, including RELA(p65), RAF-1, TGFB2, IRS1, SNCA, PIK3CD, EIF4E , and ARRB1 , confirming an inverse regulatory relationship. Conclusion This study delineates aging-related dysregulated miRNAs in idiopathic OA and highlights miR-7-5p as a key regulator of disease pathogenesis. The study highlights the Dunkin-Hartley guinea pig as a valuable translational model for exploring primary OA pathogenesis and advancing miRNA-based therapies in OA.