The transcriptional atlas, intercellular communication, and metabolic reprogramming of the cartilage and synovium in osteoarthritis patients with diabetes mellitus : a multiomics study.

Aims: A strong correlation has been observed between diabetes mellitus (DM) with the pathogenesis of osteoarthritis (OA). This study aimed to elucidate the cellular and molecular mechanisms by which DM exacerbates OA, through multiomics analysis of synovium and cartilage from OA patients with type 2 DM (T2DMOA). Methods: Single-cell RNA sequencing, bulk RNA sequencing, and metabolome profiling were performed on knee cartilage and synovium from 21 patients with OA or T2DMOA to investigate the differences in transcriptional landscape, intercellular signalling networks, transcription factor regulatory patterns, and alterations in metabolic pathways. Results: Single-cell profiling of synovium-cartilage tissues revealed distinct pathological alterations in T2DMOA patients compared to non-diabetic OA controls. In the T2DMOA synovium, we observed significantly enhanced differentiation of sublining fibroblasts into lining fibroblasts, along with enriched pathways governing energy metabolism, vasculogenesis, and cell proliferation. For cell-cell communication between cartilage and synovium, hepatocyte growth factor ( Conclusion: Our findings define a diabetes-specific OA phenotype, characterized by aberrant synovial fibroblast activation, dysregulated synovium-cartilage crosstalk, and impaired cartilage metabolism. This integrated view establishes T2DMOA as a unique metabolic-subtype of OA, driven by disrupted intercellular communication and metabolic reprogramming.