Endocrine Abstracts

Therapeutic glucocorticoids are used in rheumatoid arthritis (RA) to reduce inflammation and bone destruction. We recently reported that primary synovial fibroblasts generate active glucocorticoids via expression of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme activates cortisol from inactive cortisone (and prednisolone from prednisone) and this activity is up-regulated by inflammation. We have now examined glucocorticoid metabolism in synovial tissue explants from patients with osteoarthritis (OA) and RA to determine whether synovial tissue metabolises glucocorticoids and to identify the local and systemic consequences of this activity.

Glucocorticoid metabolism was examined in synovial tissue taken from subjects with OA (n=8) or RA (n=12) during orthopaedic surgery using radiolabelled steroids and TLC. Immunohistochemistry and RT-PCR were used to identify the cellular distribution of enzymes. The functional consequences of enzyme activity on tissue IL-6 production were examined by ELISA. Systemic corticosteroid metabolism was examined in 31 RA patients and 9 controls using GC/MS.

All synovial biopsies had substantial capacity to activate glucocorticoids confirming 11β-HSD1 expression. In RA patients, synovial cortisol generation increased with the ESR of the tissue donor (r²=0.40). 11β-HSD1 activity had functional consequences with cortisone able to decrease synovial IL-6 production (36+9% OA; 31+15% RA; both P<0.05). Steroid inactivation was also apparent in synovium suggesting the presence of 11β-HSD2 and this was confirmed by immunohistochemistry. Urinary measures of total 11β-HSD1/2 activity demonstrated high levels of 11β-HSD1 activity in untreated RA patients compared to controls. In RA patients there was a significant correlation between urinary 11β-HSD1 activity and ESR (r²=0.16).

Synovial tissue metabolises glucocorticoids with the predominant effect being glucocorticoid activation, which increases with inflammation. Endogenous glucocorticoid production in the joint is likely to have important consequences on inflammatory and bone integrity. Importantly, high glucocorticoid levels would not impact on cells expressing 11β-HSD2 and this may contribute to persistence of inflammation.