Inflammatory Molecular Networks in Age-Related Meniscus Injury: TLR/NF-κB Signaling, Immune Dysregulation, and Epigenetic Modifications

Background: The meniscus plays a crucial biomechanical role in the knee joint, and its injury often leads to degenerative joint diseases. Aging significantly increases the risk of meniscus injury, with emerging evidence suggesting dysregulated inflammatory responses as a key factor. This study investigated the inflammatory molecular mechanisms underlying age-related meniscus injury and identified potential therapeutic targets. Methods: The transcriptomic data of injured meniscus tissues from 4 young and 4 aging patients were obtained from the GEO database. Differentially expressed genes (DEGs) were analyzed and intersected with inflammation-related genes in MsigDB. Functional enrichment (GO/KEGG), protein-protein interaction (PPI) network analysis, and hub gene identification were performed. ROC curve was used to evaluate the diagnostic efficacy. We evaluated the correlations among hub genes, immune cell infiltration, RNA methylation regulators (m6A/m5C), and regulatory networks (miRNAs/TFs). Meanwhile, the expression of hub genes in the meniscus injury tissue between aging and young patients was verified by qRT-PCR and immumohistochemical staining. Results: A total of 1009 DEGs (755 upregulated and 254 downregulated) were identified in aging meniscus, with 13 inflammation-related DEGs enriched in transcription factor regulation, osteoclast differentiation, and T-helper cell pathways. Six hub genes (IFNGR2, NFKBIA, CCL22, TLR3, PLAUR, ITGA5) were identified, with NFKBIA, CCL22, and TLR3 showing high diagnostic accuracy (AUC > 0.95). In the validation samples, CCL22, NFKBIA and TLR3 were upregulated and IFNGR2, ITGA5 and PLAUR were downregulated in aging meniscus, consistent with the transcriptomic data. TLR3 strongly correlated with other hub genes (NFKBIA: R = 0.81; IFNGR2: R=-0.9). Immune cell analysis showed a decrease in activated B/T cells and an increase in dendritic cells in aging samples. NFKBIA and PLAUR were correlated with plasmacytoid dendritic cells, while CCL22 and TLR3 were negatively associated with Th1 cells. Hub genes also showed strong links with m6A/m5C regulators (YTHDC2, UHRF2, NSUN3). Regulatory network analysis implicated hsa-let-7b-5p, NFKB1, and RELA in modulating hub genes. Conclusion: Age-related meniscus injury involves inflammatory pathways, immune dysregulation, and epigenetic modifications. Hub genes (CCL22, NFKBIA, TLR3) and associated regulators (e.g., hsa-let-7b-5p, YTHDC2) may serve as diagnostic markers or therapeutic targets for age-related meniscus injury.