Synovial expression of glucocorticoid receptor parallels fibroblast activation in patients with rheumatoid arthritis

Abstract Background Hypocortisolemia is associated with increased expression of NR3C1 (glucocorticoid receptor, GR) in blood cells. As endogenous cortisol production is decreased in some RA patients, we tested the hypothesis that GR may be aberrantly expressed in rheumatoid synovium. Methods We defined the cellular pattern of NR3C1 synovial expression using human and mouse single‐cell RNA‐sequencing data. Bulk synovial RNA‐sequencing data from early ( n = 57) or established ( n = 94) RA were compared to osteoarthritis ( n = 22) and healthy synovium ( n = 28). Results GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11β‐HSD1/11β‐HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene‐sets, including ‘inflammatory response’, ‘IFN‐γ response’ and ‘IL6/JAK/STAT3 signalling’. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state. Conclusions GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.