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Submitted on May 25, 2004
Accepted on December 1, 2004
-Hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. Division of Medical Science, Institute of Biomedical Research, The University of Birmingham, Birmingham, B15 2TT, United Kingdom. Department of Pathology, Sapporo Medical College, Sapporo, Japan
* To whom correspondence should be addressed. E-mail: j.vanleeuwen{at}erasmusmc.nl.
11
-hydroxysteroid dehydrogenase type 1 (11-HSD1) plays an important role in the pre-receptor regulation of corticosteroids by locally converting cortisone into active cortisol. To investigate the impact of this mechanism on osteoblast development we have characterized 11-HSD1 activity and regulation in a differentiating human osteoblast cell-line (SV-HFO). Continuous treatment with the synthetic glucocorticoid dexamethasone (DEX) induces differentiation of SV-HFO cells during 21 days culture. Using this cell system we showed an inverse relationship between 11-HSD1 activity and osteoblast differentiation. 11-HSD1 mRNA expression and activity were low and constant in differentiating osteoblasts. However, in the absence of differentiation (no DEX) 11-HSD1 mRNA and activity increased strongly from day 12 of culture onwards with a peak around day 19. Promoter reporter studies provided evidence that specific regions of the 11-HSD1 gene are involved in this differentiation controlled regulation of the enzyme. Functional implication of these changes in 11-HSD1 is shown by the induction of osteoblast differentiation in the presence of cortisone. The current study demonstrates the presence of an intrinsic differentiation-driven molecular switch that controls expression and activity of 11-HSD1 and thereby cortisol production by human osteoblasts. This efficient mechanism by which osteoblasts generate cortisol in an autocrine fashion to ensure proper differentiation will help to understand the complex effects of cortisol on bone metabolism.
-hydroxysteroid dehydrogenase
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