Circular RNAs coordinate immunomodulation in osteoarthritic cartilage via antigen presentation and adaptive immune response

BACKGROUND: Osteoarthritis (OA) is now recognized as a process involving chronic low-grade inflammation and coordinated immune responses. Circular RNAs (circRNAs) are potent regulators of immunity in cancer and autoimmunity, yet their roles in OA remain largely undefined. This study aimed to characterize the circRNA landscape in human OA cartilage and investigate their roles in modulating joint immunity. RESULTS: rRNA-depleted RNA sequencing of paired damaged and preserved cartilage from OA patients identified 179 differentially expressed circRNAs (DECs). Co-expression and gene-set enrichment analyses revealed that specific differentially expressed circRNAs (DECs), including circPTK2-OA, hsa-intergenic_00316, and hsa-HLA-DRB1_0002, were significantly associated with key immune processes, including leukocyte migration, chemotaxis, and antigen presentation via MHC class II. Furthermore, competitive endogenous RNA (ceRNA) network analysis highlighted key circRNAs, such as the downregulated hsa-UROS_0001, which was linked to extracellular matrix integrity. In contrast, the upregulated hsa-DAPK2_0010 exhibited the most extensive interactions and was associated with ossification and immune regulation. CONCLUSIONS: Our findings demonstrate a dynamically regulated circRNA landscape in OA. Specific DECs appear to orchestrate joint immunity by potentially enhancing antigen presentation and macrophage polarization, thereby facilitating T-cell activation. These results position circRNAs as unrecognized immunoregulators in OA, nominating them as candidate biomarkers or therapeutic targets for modulating the joint immune microenvironment.