Abstract
Isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) act at a prereceptor level to regulate the tissue-specific availability of active glucocorticoids. To examine the effect of this on cell proliferation and differentiation, we have developed transfectant variants of a rat osteosarcoma cell line that express cDNA for 11beta-HSD1 (ROS 17/2.8beta1) or 11beta-HSD2 (ROS 17/2.8beta2). ROS 17/2.8beta1 showed net conversion of cortisone to cortisol whereas ROS 17/ 2.8beta2 showed only inactivation of cortisol to cortisone. There was no significant difference in glucocorticoid receptor (GR) expression between the different clones. However, in proliferation and differentiation studies, ROS 17/ 2.8beta2 cells were completely resistant to cortisol. In contrast, ROS 17/ 2.8beta1 were sensitive to both cortisone and cortisol. Expression of 11beta-HSD1 decreased cell proliferation whereas 11beta-HSD2 increased proliferation. These responses appear to be due to metabolism of endogenous serum glucocorticoids; proliferation of ROS 17/ 2.8beta1 decreased further with exogenous cortisone or cortisol whereas ROS 17/ 2.8beta2 were resistant to both compounds. The pro-proliferative effects of 11beta-HSD2 were abrogated by 18beta-glycyrrhetinic acid, an 11beta-HSD inhibitor, and in cells transfected with cDNA encoding inactive 11beta-HSD2. Data indicate that differential regulation of 11beta-HSD1 and 2 (rather than GR expression) is a key determinant of cell proliferation. Dysregulated expression of 11beta-HSD2 may be a novel feature of tumorigenesis.
Original language | English |
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Pages (from-to) | 36-44 |
Number of pages | 9 |
Journal | FASEB Journal |
Volume | 16 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jan 2002 |
Keywords
- 11 beta-HSD
- intracrine
- glucocorticoid metabolism
- glucocorticoid receptor