Distinct periarticular muscle transcriptomes: inflammation in rheumatoid arthritis versus metabolic dysregulation in...

Periarticular skeletal muscle abnormalities are recognised in rheumatoid arthritis (RA) and osteoarthritis (OA), but their divergent molecular pathologies are poorly defined. This study aimed to elucidate and directly compare the transcriptomic profiles of periarticular muscle in patients with RA and OA.

We performed bulk RNA sequencing of periarticular skeletal muscle samples collected during total joint arthroplasty from RA (n=6) and OA (n=4) patients. Differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), pathway enrichment, and gene set variation analyses were conducted to identify disease-specific molecular features and their clinical associations.

The two conditions showed fundamentally distinct profiles. RA muscle exhibited a pronounced inflammatory signature, characterised by upregulation of cytokine-responsive genes including FOS, EGR1, and CXCL2, and enrichment of tumour necrosis factor-α and interleukin-6 (IL-6)/JAK-STAT3 signalling. In contrast, OA muscle was characterised by metabolic dysregulation, with upregulation of genes linked to adipogenesis (PCK1, SFRP4) and significant enrichment of epithelial-to-mesenchymal transition (EMT) signalling. These divergent profiles were further supported by WGCNA, which identified distinct modules reflecting heightened innate immune and complement activation in RA, and disrupted metabolic processes in OA. Notably, in RA, the IL-2-STAT5 signalling pathway was unique among those tested in showing a strong positive correlation with DAS28-ESR (r=0.94, p=0.019).

This study reveals distinct molecular pathologies in the periarticular muscle of RA and OA. RA muscle shows an intense inflammatory profile potentially linked to cachexia, whereas OA muscle displays features of metabolic disease and pro-fibrotic remodelling.