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LncRNA NONHSAT248596.1 Promotes Osteoarthritis via miR-146a-5p/CXCR4 Axis by Inducing Chondrocyte Apoptosis and Extracellular Matrix Degradation

Year: 2025

Type: article

Abstract: Objective: Osteoarthritis (OA) is characterized by articular cartilage degeneration, osteophyte formation, subchondral bone remodeling, synovitis, and joint capsule fibrosis, yet its underlying molecular mechanisms and the functional roles of long non-coding RNAs (lncRNAs) remain poorly understood. This study aimed to investigate the role of lncRNA NONHSAT248596.1 in the pathogenesis of OA through the miR-146a-5p/CXCR4 axis. Materials and Methods: The experimental systems included human articular cartilage samples, a rabbit model of OA, and chondrocytes treated with 100 ng/mL SDF-1. DIANA software predicted lncRNAs targeting the miR-146a-5p/CXCR4 axis. Dual-luciferase reporter assay verified the molecular interactions. The expression levels of target genes and proteins (CXCR4, miR-146a-5p, NONHSAT248596.1, TNF-α, IL-1β, MMP-13, collagen II, and aggrecan) were analyzed using qRT-PCR, Western blotting, and ELISA both in vitro and in vivo. Cell viability and apoptosis were measured by CCK-8 assay and flow cytometry, respectively. Cartilage pathology in the rabbit models was assessed via safranin O and hematoxylin and eosin staining at 4, 8, and 12 weeks. Results: LncRNA NONHSAT248596.1 was significantly upregulated in OA patients and in SDF-1-induced chondrocytes. The dual-luciferase assays confirmed that NONHSAT248596.1 interacted with miR-146a-5p, and miR-146a-5p interacted with CXCR4 in OA. Overexpression of NONHSAT248596.1 promoted chondrocyte apoptosis (p < 0.0001, n=3), upregulated MMP-13 (p < 0.0001, n=3), and downregulated collagen II (p < 0.0001, n=3) and aggrecan (p < 0.01, n=3), while exacerbating cartilage degradation (p < 0.05, n=3/group/time point). Silencing NONHSAT248596.1 or overexpressing miR-146a-5p reduced chondrocyte apoptosis and extracellular matrix degradation in vitro , which also ameliorated cartilage degradation (Mankin score: 5.9± 1.7 VS 2.4± 0.59, p< 0.0001, n=3/group/time point) in rabbit OA models. Conclusion: LncRNA NONHSAT248596.1 promotes OA via miR-146a-5p/CXCR4 axis by inducing chondrocyte apoptosis and extracellular matrix degradation. These results identify NONHSAT248596.1 as a potential therapeutic target for OA intervention and underscore the miR-146a-5p/CXCR4 axis as a critical regulatory pathway for cartilage protection. Keywords: osteoarthritis, competing endogenous RNA, lncRNA NONHSAT248596.1, CXCR4, miR-146a-5p, chondrocyte apoptosis, extracellular matrix degradation

Source: Journal of Inflammation Research

DOI: 10.2147/jir.s558704