Multi-omics analysis unveils inflammatory and metabolic alterations between the synovium and cartilage in patients with knee osteoarthritis.

Background: KOA (knee osteoarthritis) is a degenerative disease affecting the entire joint, involving synovial inflammation and cartilage degeneration, but their molecular interplay remains unclear. This study integrated proteomics and metabolomics to investigate cross-tissue alterations in KOA. Methods: Paired synovial and cartilage tissues from 12 KOA patients and 12 controls were analyzed using DIA proteomics and untargeted metabolomics. The major molecular abnormalities in OA synovium and cartilage were evaluated through differential expression analysis, GO and KEGG functional enrichment analyses, protein-protein interaction network analysis, protein-metabolite integrated analysis, and cross-tissue integrative analysis. TIAM1, Rac1, and MRPS7 were validated by Western blot. Results: Proteomic analysis showed that proteins related to inflammation and cytoskeletal remodeling were significantly upregulated in OA synovial tissue, including increased expression of TIAM1. In cartilage tissue, proteins related to mitochondrial translation and energy metabolism were significantly downregulated, including decreased expression of MRPS7. Metabolomic analysis indicated enhanced arachidonic acid metabolism in synovial tissue, with significantly increased levels of inflammation-related metabolites such as PGE2 and 12-HETE. In cartilage tissue, metabolites related to the tricarboxylic acid cycle and pyrimidine metabolism were decreased, suggesting impaired energy supply and nucleotide metabolism. Protein-metabolite integrated analysis further showed that the differential molecules in OA synovium were mainly involved in inflammatory signaling, nucleotide metabolism, carbohydrate metabolism, and lipid mediator output, whereas those in OA cartilage were mainly associated with mitochondrial function, basal metabolism, cellular stress, and matrix homeostasis-related processes. Integrated analysis suggested that the synovial TIAM1/Rac1-related pathway may be involved in the inflammatory microenvironment and cytoskeletal remodeling, whereas the downregulation of MRPS7 in cartilage indicates suppressed mitochondrial translation. Western blot results further validated the upregulation of TIAM1 and Rac1 in OA synovium and the downregulation of MRPS7 in OA cartilage. Conclusion: This multi omics study revealed the cross tissue molecular characteristics of KOA, manifested as synovitis metabolic activation and cartilage energy metabolism dysfunction, suggesting that it may be closely related to the regulation of TIAM1-Rac1 signaling axis and mitochondrial damage. These findings provide a new perspective for a deeper understanding of the pathogenesis of KOA and point out potential therapeutic intervention targets.