Local and systemic glucocorticoid metabolism in inflammatory arthritis

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@article{3c1ae5d4cd2f44e895e21f4862a7b611,
title = "Local and systemic glucocorticoid metabolism in inflammatory arthritis",
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.",
author = "Rowan Hardy and Elizabeth Rabbitt and Andrew Filer and P Emery and M Hewison and Paul Stewart and Neil Gittoes and Christopher Buckley and Karim Raza and Mark Cooper",
year = "2008",
month = jan,
day = "1",
doi = "10.1136/ard.2008.090662",
language = "English",
volume = "67",
pages = "1204--1210",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "9",

}

RIS

TY - JOUR

T1 - Local and systemic glucocorticoid metabolism in inflammatory arthritis

AU - Hardy, Rowan

AU - Rabbitt, Elizabeth

AU - Filer, Andrew

AU - Emery, P

AU - Hewison, M

AU - Stewart, Paul

AU - Gittoes, Neil

AU - Buckley, Christopher

AU - Raza, Karim

AU - Cooper, Mark

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

U2 - 10.1136/ard.2008.090662

DO - 10.1136/ard.2008.090662

M3 - Article

C2 - 18420938

VL - 67

SP - 1204

EP - 1210

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 9

ER -