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Isolated, primary synovial fibroblasts generate active glucocorticoids through expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This enzyme produces cortisol from inactive cortisone (and prednisolone from prednisone).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).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 11beta-HSD enzymes. Systemic glucocorticoid metabolism was examined in patients with RA using gas chromatography/mass spectrometry.Synovial tissue synthesised cortisol from cortisone, confirming functional 11beta-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 11beta-HSD2 expression in synovial macrophages, whereas 11beta-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 11beta-HSD1 activity in untreated patients with RA compared with controls and a significant correlation between total body 11beta-HSD1 activity and ESR.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.

Original publication

DOI

10.1136/ard.2008.090662

Type

Journal article

Journal

Annals of the rheumatic diseases

Publication Date

09/2008

Volume

67

Pages

1204 - 1210

Addresses

Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.

Keywords

Synovial Membrane, Synovial Fluid, Humans, Arthritis, Rheumatoid, Osteoarthritis, Cortisone, Hydrocortisone, 11-beta-Hydroxysteroid Dehydrogenase Type 1, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Interleukin-6, Enzyme Inhibitors, Glucocorticoids, Tissue Culture Techniques, Aged, Middle Aged, Female, Male