Local and systemic glucocorticoid metabolism in inflammatory arthritis

Research output: Contribution to journalArticle

Abstract

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

Details

Original languageEnglish
Pages (from-to)1204-1210
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume67
Issue number9
Publication statusPublished - 1 Jan 2008