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Ann Rheum Dis 2008;67:1204-1210 doi:10.1136/ard.2008.090662
  • Extended report

Local and systemic glucocorticoid metabolism in inflammatory arthritis

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  1. R Hardy1,
  2. E H Rabbitt1,
  3. A Filer2,
  4. P Emery3,
  5. M Hewison4,
  6. P M Stewart1,
  7. N J Gittoes1,
  8. C D Buckley2,
  9. K Raza2,
  10. M S Cooper1
  1. 1
    Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK
  2. 2
    Rheumatology, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK
  3. 3
    Academic Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
  4. 4
    Department of Orthopedic Surgery, UCLA-Orthopedic Hospital, Los Angeles, California, USA
  1. Dr M S Cooper, Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK; M.S.Cooper{at}bham.ac.uk
  • Accepted 9 April 2008
  • Published Online First 17 April 2008

Abstract

Background: Isolated, primary synovial fibroblasts generate active glucocorticoids through expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-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 11β-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 11β-HSD2 expression in synovial macrophages, whereas 11β-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 11β-HSD1 activity in untreated patients with RA compared with controls and a significant correlation between total body 11β-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.

Footnotes

  • ‣ Additional tables are published online only at http://ard.bmj.com/content/vol67/issue9

  • Funding: This study was funded by the Arthritis Research Campaign (project grant number 18081) and the Medical Research Council, UK.

  • Competing interests: None.

  • Ethics approval: Approved by the local ethics committee.

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