Molecular mechanisms of synovial pathology in osteoarthritis: insights from CXCL10 and MC4R expression
Tao Yang1,2,3, Hong Liu2,3, Jian Chen4,5,6
1Graduate School, Jinzhou Medical University, No. 40, Songpo Road, Linghe District, Jinzhou, 121001, Liaoning, China.
Abstract:
Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain unclear. This study integrated bioinformatics and experimental validation to identify key genes in OA synovium and their association with immune infiltration. Analysis of the GSE82107 dataset (10 OA, 7 controls) revealed 909 differentially expressed genes (525 upregulated, 384 downregulated). WGCNA identified the "midnightblue" module, and its intersection with DEGs yielded 122 genes enriched in cytokine-cytokine receptor interaction, JAK-STAT signaling, and autophagy pathways. Protein-protein interaction analysis highlighted FLT3LG, MC4R, CXCL10, CARTPT, and LHX2 as core genes (AUC 0.743-0.871). Immune infiltration analysis showed elevated M0 macrophages in OA, with CXCL10 showing a strong positive correlation with M1 macrophage infiltration (r = 0.74), and MC4R correlating with the presence of follicular helper T cells (r = 0.85). In vitro, OA-derived fibroblast-like synoviocytes exhibited CXCL10 upregulation, MC4R downregulation, and increased IL-6, IL-8, and TNF-α secretion, which were markedly reduced by CXCL10 knockdown or MC4R overexpression. Synovial tissue assays confirmed these expression patterns. CXCL10 and MC4R may represent promising diagnostic markers and therapeutic targets, offering new insights into OA immunopathogenesis and precision intervention.
Insights
This study identifies CXCL10 and MC4R as key genes in osteoarthritis (OA) pathogenesis, linking them to immune cell infiltration and inflammation. These genes show potential as diagnostic markers and therapeutic targets for OA.
Area of Science:
- Biomedical research
- Molecular biology
- Immunology
Background:
- Osteoarthritis (OA) is a prevalent joint disorder with unclear molecular underpinnings.
- Synovial inflammation and cartilage degeneration are hallmarks of OA.
Purpose of the Study:
- To identify key genes in OA synovium using bioinformatics and experimental validation.
- To investigate the association between these genes and immune infiltration in OA.
Main Methods:
- Differential gene expression analysis of the GSE82107 dataset.
- Weighted Gene Co-expression Network Analysis (WGCNA) to identify relevant gene modules.
- Protein-protein interaction network analysis to pinpoint core genes.
- Immune infiltration analysis and correlation studies.
- In vitro experiments with OA synoviocytes and synovial tissue assays.
Main Results:
- Identified 909 differentially expressed genes in OA synovium.
- Highlighted FLT3LG, MC4R, CXCL10, CARTPT, and LHX2 as core genes.
- Found elevated M0 macrophages in OA; CXCL10 correlated with M1 macrophages (r=0.74).
- MC4R correlated with follicular helper T cells (r=0.85).
- CXCL10 was upregulated and MC4R downregulated in OA synoviocytes, increasing inflammatory cytokines.
Conclusions:
- CXCL10 and MC4R are significantly implicated in osteoarthritis immunopathogenesis.
- These genes demonstrate potential as diagnostic biomarkers for OA.
- CXCL10 and MC4R represent promising therapeutic targets for precision intervention in OA.
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