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Division of Medical Sciences, Institute of Clinical Research, Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, UK
1Correspondence: Department of Medicine, Institute of Clinical Research, Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, UK. E-mail: M.Hewison{at}bham.ac.uk
Isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-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 11ß-HSD1 (ROS 17/2.8ß1) or 11ß-HSD2 (ROS 17/2.8ß2). ROS 17/2.8ß1 showed net conversion of cortisone to cortisol whereas ROS 17/2.8ß2 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 17/2.8ß2 cells were completely resistant to cortisol. In contrast, ROS 17/2.8ß1 were sensitive to both cortisone and cortisol. Expression of 11ß-HSD1 decreased cell proliferation whereas 11ß-HSD2 increased proliferation. These responses appear to be due to metabolism of endogenous serum glucocorticoids; proliferation of ROS 17/2.8ß1 decreased further with exogenous cortisone or cortisol whereas ROS 17/2.8ß2 were resistant to both compounds. The pro-proliferative effects of 11ß-HSD2 were abrogated by 18ß-glycyrrhetinic acid, an 11ß-HSD inhibitor, and in cells transfected with cDNA encoding inactive 11ß-HSD2. Data indicate that differential regulation of 11ß-HSD1 and 2 (rather than GR expression) is a key determinant of cell proliferation. Dysregulated expression of 11ß-HSD2 may be a novel feature of tumorigenesis.—Rabbitt, E. H., Lavery, G. G., Walker, E. A., Cooper, M. S., Stewart, P. M., Hewison, M. Prereceptor regulation of glucocorticoid action by 11ß-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation.
Key Words: 11ß-HSD • glucocorticoid metabolism • glucocorticoid receptor • intracrine
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