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Endocrinology Vol. 142, No. 3 1341-1348
Copyright © 2001 by The Endocrine Society

ARTICLES

Cloning and in Vitro Characterization of {alpha}1(I)-Collagen 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Transgenes as Models for Osteoblast-Selective Inactivation of Natural Glucocorticoids1

Henning W. Woitge, John R. Harrison, Ante Ivkosic, Zygmunt Krozowski and Barbara E. Kream

Department of Medicine, School of Medicine (H.W.W., A.I., B.E.K.), and Department of Orthodontics, School of Dental Medicine (J.R.H.), University of Connecticut Health Center, Farmington, Connecticut 06030; and Laboratory of Molecular Hypertension, Baker Medical Research Institute (Z.K.), Prahran 3181, Australia

Address all correspondence and requests for reprints to: Barbara E. Kream, Ph.D., Department of Medicine, MC-1850, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030. E-mail: kream{at}nso1.uchc.edu

The NAD-dependent enzyme, 11{beta}-hydroxysteroid dehydrogenase type II (11{beta}HSD2), catalyzes the unidirectional conversion of biologically active glucocorticoids to inactive metabolites. In vivo, 11{beta}HSD2 protects the mineralocorticoid receptor from activation by glucocorticoids in mineralocorticoid target tissues such as kidney. The goal of the present study was to use targeted overexpression of 11{beta}HSD2 as a novel means of disrupting glucocorticoid signaling in osteoblastic cells. Rat 11{beta}HSD2 complementary DNA was cloned downstream of a 2.3- and 3.6-kb {alpha}1(I)-collagen (Col1a1) promoter fragment to produce the expression plasmids Col2.3-HSD2 and Col3.6-HSD2, respectively, which were transiently and/or stably transfected in osteoblastic ROS 17/2.8 and MC3T3-E1 cells. Transgene messenger RNA and protein were detected in transfected cells by Northern blot analysis and immunostaining, respectively. Transfection of 11{beta}HSD2 led to higher rates of conversion of [3H]corticosterone to [3H]dehydrocorticosterone and reduced glucocorticoid-dependent regulation of a mouse mammary tumor virus promoter-reporter construct, cell growth, and messenger RNA markers compared with transfection of a control vector. Expression of 11{beta}HSD2 under the control of Col1a1 promoter fragments may provide a novel model to study the role of glucocorticoid signaling in osteoblastic cells.




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