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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 12 5401-5407
Copyright © 2002 by The Endocrine Society

Special Feature

Human Osteoblast-Like Cells Express Predominantly Steroid 5{alpha}-Reductase Type 1

Sedika Issa, Doris Schnabel, Maritta Feix, Lutz Wolf, Hans-Eckart Schaefer, David W. Russell and Hans-Udo Schweikert

Department of Internal Medicine, University of Bonn (S.I., D.S., M.F., H.U.S.), Bonn, Germany; Department of Orthopedics, St. Petrus Krankenhaus (L.W.), 53113 Bonn, Germany; Department of Pathology, University of Freiburg (H.E.S.), 79002 Freiburg, Germany; and Department of Molecular Genetics, University of Texas Southwestern Medical Center (D.W.R.), Dallas, Texas 75390-9046

Address all correspondence and requests for reprints to: Hans-Udo Schweikert, M.D., Endocrinology, Department of Internal Medicine, University of Bonn, Wilhelmstrasse 35-37, 53111 Bonn, Germany.

Abstract

In previous studies we established that human bone and human osteoblast-like cells (hOB cells) cultured from bone express 5{alpha}-reductase (5{alpha}-R) activity, as demonstrated by the conversion of testosterone and androstenedione to their corresponding 5{alpha}-reduced metabolites, 5{alpha}-dihydrotestosterone (DHT) and 5{alpha}-androstanedione. Two 5{alpha}-R isozymes (types 1 and 2) have been identified in various tissues. As their nature in bone is unknown, we investigated which isozymes were expressed in first passage hOB cells cultured from bone specimens obtained from six donors (five women and one man). For comparison, 5{alpha}-reductase isozyme expression in genital skin fibroblasts cultured from foreskin of three males was determined. Pharmacological and biochemical studies using selective inhibitors of the 5{alpha}-R isozymes were performed, and gene expression was assessed by RT-PCR. In hOB cells, LY191704, a potent nonsteroidal selective inhibitor of 5{alpha}-R type 1, and the 4-azasteroid 17ß-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5{alpha}-androstan-3-one (a dual inhibitor of 5{alpha}-R types 1 and 2) inhibited 5{alpha}-R activity with a 50% inhibitory concentration (IC50) of approximately 4 nM. Finasteride, a selective inhibitor of 5{alpha}-R type 2, blocked 5{alpha}-R activity with an IC50 of approximately 60 nM. The IC50 of progesterone, a physiological substrate for 5{alpha}-R, was approximately 200 nM. In genital skin fibroblasts, LY191704 inhibited 5{alpha}-R with an IC50 of more than 5000 nM, whereas finasteride and 17ß-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5{alpha}-androstan-3-one effectively inhibited 5{alpha}-R with IC50 of approximately 4 nM. Experiments to determine 5{alpha}-reductase activity in homogenates of hOB cells as a function of pH showed very low activity at pH 5.5, but a broad shoulder of activity from pH 6.0–9.0, which was not inhibited by finasteride, but was nearly completely blocked by LY191704. RT-PCR revealed that 5{alpha}-R type 1 and 2 mRNAs were expressed in both bone and genital skin fibroblasts. Based on our pharmacological and biochemical studies, it appears that 5{alpha}-R activity in hOB cells is catalyzed predominantly by the type 1 rather than the type 2 isozyme. This expression pattern is in contrast to that in genital skin fibroblasts, where the activity of the type 2 isozyme prevails. As in most androgen target tissues DHT is biologically more active as an androgen than testosterone, DHT is formed in bone by 5{alpha}-R type 1 action from circulating testosterone, and bone cells also express the androgen receptor, local DHT production may play a physiological role in human bone homeostasis.




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