Context: We have shown that isolated, primary synovial fibroblasts generate active glucocorticoids via expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme produces cortisol from inactive cortisone (and prednisolone from prednisone).
Objective: We have now examined glucocorticoid metabolism in patients with RA to determine how intact synovial tissue metabolizes glucocorticoids and to identify the local and systemic consequences of this activity.
Methods: Synovial tissue was taken from subjects with RA during joint replacement surgery. Glucocorticoid metabolism in explants was assessed using thin layer chromatography and specific enzyme inhibitors. RT-PCR and immunohistochemistry were used to determine expression and distribution of 11β-HSD enzymes. Systemic glucocorticoid metabolism was examined in RA subjects using gas chromatography/mass spectrometry.
Results: Synovial tissue synthesized cortisol from cortisone confirming functional 11β-HSD1 expression. In patients with RA, enzyme activity correlated with donor ESR. Synovial tissues were also able to convert cortisol back to cortisone. Inhibitor studies and immunohistochemistry suggested this was due to 11β-HSD2 expression in synovial macrophages, whereas 11β-HSD1 expression was primarily in fibroblasts. Synovial fluids exhibited lower cortisone levels compared to matched serum indicating net local steroid activation. Urinary analyses indicated high 11&beta]-HSD1 activity in untreated RA patients compared to controls and a significant correlation between total body 11β-HSD1 activity and ESR.
Conclusions: Synovial tissue metabolizes glucocorticoids, the predominant effect being glucocorticoid activation, and this increases with inflammation. Endogenous glucocorticoid production in the joint is likely to impact on local inflammation and bone integrity.
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