Synovial Metal Binding Proteins in Haemophilic Arthropathy: Potential Biomarkers and Therapeutic Targets

Abstract

BACKGROUND: Haemophilic arthropathy (HA) is a chronic joint disease in haemophiliac patients, driven by recurrent bleeding and distinct from osteoarthritis (OA) and rheumatoid arthritis (RA) in its pathogenesis, including metal ion accumulation and inflammatory responses. AIM: To explore the role of metal ion binding proteins in HA and identify potential biomarkers and therapeutic targets. METHODS: Synovial tissues from 21 patients (7 HA, 7 OA, 7 RA) were analysed using data-independent acquisition proteomics. Differentially expressed proteins were identified (fold change >2, p < 0.05) and analysed through Gene Ontology, KEGG pathways, and protein-protein interaction networks. Iron concentrations were measured via ICP-MS, and selected proteins (SOD2, CA1) were validated by immunofluorescence. RESULTS: HA synovial tissue showed 123 and 124 differentially expressed metal binding proteins versus OA and RA, respectively, with 29 overlapping proteins. Enriched functions included iron ion binding, magnesium ion binding, calcium ion binding, zinc ion binding and copper ion binding. Key pathways involved carbon metabolism, the TCA cycle, oxidative phosphorylation, and extracellular matrix remodelling. PPI analysis highlighted hub proteins, including SOD2, NDUFS1, ACO2, IDH3A, MMP1, COL1A1, COL1A2, and LOX. ICP-MS confirmed elevated iron in HA tissues, and immunofluorescence validated protein expression trends. CONCLUSION: Metal binding proteins are central to HA pathogenesis, influencing oxidative stress, mitochondrial function, and extracellular matrix remodelling. These findings provide potential biomarkers and therapeutic targets for synovial-targeted regulation of metal ion homeostasis in HA.