RESEARCH - Local and systemic glucocorticoid metabolism in inflammatory arthritis

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Ann Rheum Dis. Published Online First: 17 April 2008.

doi:10.1136/ard.2008.090662

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Extended Report

Local and systemic glucocorticoid metabolism in inflammatory arthritis

Rowan S Hardy 1, H Rabbitt 1, Filer 2, Emery 3,

Hewison 4, M 1, Neil Gittoes 1, D

Buckley 1, Karim Raza 1 and Mark S 1*

1 University of Birmingham, United Kingdom

2 university of Birmingham, United Kingdom

3 University of Leeds, United Kingdom

4 UCLA-Orthopedic Hospital, United States

Abstract

Context: We have shown that isolated, primary synovial fibroblasts

generate active glucocorticoids via expression of 11-hydroxysteroid

dehydrogenase type 1 (11-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 11-HSD enzymes. Systemic glucocorticoid

metabolism was examined in RA subjects using gas chromatography/mass

spectrometry.

Results: Synovial tissue synthesized cortisol from cortisone

confirming functional 11-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 11-HSD2 expression in

synovial macrophages, whereas 11-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 11-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.

http://ard.bmj.com/cgi/content/abstract/ard.2008.090662v1?papetoc

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