title: Local and systemic glucocorticoid metabolism in inflammatory arthritis.
abstract: BACKGROUND
  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).
  
  
  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 11beta-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 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.
  
  
  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.
authors.affiliation: Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hardy
authors.forename: E H
authors.initials: EH
authors.lastname: Rabbitt
authors.forename: A
authors.initials: A
authors.lastname: Filer
authors.forename: P
authors.initials: P
authors.lastname: Emery
authors.forename: M
authors.initials: M
authors.lastname: Hewison
authors.forename: P M
authors.initials: PM
authors.lastname: Stewart
authors.forename: N J
authors.initials: NJ
authors.lastname: Gittoes
authors.forename: C D
authors.initials: CD
authors.lastname: Buckley
authors.forename: K
authors.initials: K
authors.lastname: Raza
authors.forename: M S
authors.initials: MS
authors.lastname: Cooper
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism / Q000502:physiology; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000378:metabolism*; D003348:Cortisone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D015850:Interleukin-6; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003348:Cortisone; D006854:Hydrocortisone