ISSN 1470-3947 (print)
ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology

Published by BioScientifica
Endocrine Abstracts (2006) 11 P27 
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Synergistic induction of osteoblastic local glucocorticoid metabolism by inflammatory cytokines and glucocorticoids: a novel mechanism for glucocorticoid-induced bone disease

K Kaur, R Hardy, PM Stewart, EH Rabbitt, M Hewison & MS Cooper

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When used to treat inflammatory disease therapeutic glucocorticoids (GCs) cause rapid bone loss. However clinical studies suggest that in patients without inflammation GCs have little impact on the skeleton. The mechanism by which inflammation magnifies the effects of GCs is unknown. We have proposed that intracellular GC generation (inactive cortisone/prednisone to active cortisol/prednisolone conversion) via the 11 beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) enzyme determines the clinical effects of GCs on bone. In healthy subjects the effect of prednisolone on bone formation markers is predicted by measures of 11b-HSD1 activity. We have now examined the hypothesis that the modifying effect of inflammation is due to increased local GC generation in human osteoblasts. In MG63 osteosarcoma cells and primary osteoblasts IL-1 and TNFa potently induced 11b-HSD1 expression and activity (100 to 200-fold) whereas DEX treatment only mildly increased expression (10 to 50-fold). However, when combined with IL-1 or TNFa, DEX synergistically induced 11b-HSD1 expression and activity (1500-fold). Similar induction was also seen in primary cultures of human fibroblasts from bone marrow and synovium. This effect was specific for 11b-HSD1 with DEX inhibiting the cytokine induction of other genes such as OPG and COX-2. GC receptor alpha and beta and H6PDH (11b-HSD1 cofactor generating enzyme) expression were unchanged. Time course and actinomycin D studies showed that the synergistic effect of cytokines and GCs on 11b-HSD1 expression is transcriptional. Promoter-reporter analyses indicated that an AP-1 site in the 11b-HSD1 proximal promoter mediated the induction of activity with cytokines. However, DEX and cortisol suppressed IL-1/TNFa-induced luciferase activity, suggesting a novel mechanism for synergistic induction of 11b-HSD1 expression. In response to inflammation 11b-HSD1 activity increases in osteoblasts. This effect is magnified by GC treatment. Inflammatory cytokine/GC synergism of 11b-HSD1 induction is a potential mechanism to explain the modifying effect of inflammation on GC-induced bone loss.

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