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Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss
  1. K Kaur1,
  2. R Hardy1,
  3. M M Ahasan1,
  4. M Eijken2,
  5. J P van Leeuwen2,
  6. A Filer3,
  7. A M Thomas4,
  8. K Raza3,
  9. C D Buckley3,
  10. P M Stewart1,
  11. E H Rabbitt1,
  12. M Hewison5,
  13. M S Cooper1
  1. 1School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham, UK
  2. 2Department Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  3. 3School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, UK
  4. 4Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK
  5. 5Department of Orthopedic Surgery, UCLA-Orthopedic Hospital, Los Angeles, California, USA
  1. Correspondence to Dr Mark S Cooper, Endocrinology, School of Clinical and Experimental Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK; M.S.Cooper{at}


Objectives Synovial fibroblasts and osteoblasts generate active glucocorticoids by means of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. This activity increases in response to proinflammatory cytokines or glucocorticoids. During inflammatory arthritis synovium and bone are exposed to both these factors. This study hypothesised that glucocorticoids magnify the effects of inflammatory cytokines on local glucocorticoid production in both synovium and bone.

Methods The effects of inflammatory cytokines (IL-1β/tumour necrosis factor alpha; TNFα) and glucocorticoids, alone or combined, were assessed on the expression and activity of 11β-HSD1 in primary synovial fibroblasts, primary human osteoblasts and MG-63 osteosarcoma cells. A range of other target genes and cell types were used to examine the specificity of effects. Functional consequences were assessed using IL-6 ELISA.

Results In synovial fibroblasts and osteoblasts, treatment with cytokines or glucocorticoids in isolation induced 11β-HSD1 expression and activity. However, in combination, 11β-HSD1 expression, activity and functional consequences were induced synergistically to a level not seen with isolated treatments. This effect was seen in normal skin fibroblasts but not foreskin fibroblasts or adipocytes and was only seen for the 11β-HSD1 gene. Synergistic induction had functional consequences on IL-6 production.

Conclusions Combined treatment with inflammatory cytokines and glucocorticoids synergistically induces 11β-HSD1 expression and activity in synovial fibroblasts and osteoblasts, providing a mechanism by which synovium and bone can interact to enhance anti-inflammatory responses by increasing localised glucocorticoid levels. However, the synergistic induction of 11β-HSD1 might also cause detrimental glucocorticoid accumulation in bone or surrounding tissues.

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  • KK and RH contributed equally.

  • Funding This study was funded by the Medical Research Council, UK and the Arthritis Research Campaign Project grants 17730 and 18081.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the South Birmingham Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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