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Transcriptional Up-Regulation of the Human Androgen Receptor by Androgen in Bone Cells¹

Bone and Mineral Research Unit, Veterans Affairs Medical Center, (K.M.W., X.Z., E.S.O.) Portland, Oregon 97201; the Departments of Behavioral Neuroscience (K.M.W.), Cell and Developmental Biology (K.M.W.), Medicine (K.M.W. and E.S.O.), Pharmacology (E.K.), and Surgery (E.K.), Oregon Health Sciences University, Portland, Oregon 97201; and the Department of Medicine, Comprehensive Cancer Center and Endocrinology-Reproductive Physiology Program, University of Wisconsin (C.C.), Madison, Wisconsin 53792

Address all correspondence and requests for reprints to: Kristine Wiren, Ph.D., Research Service 151Q, Veterans Administration Medical Center, 3710 SW Veterans Hospital Road, Portland, Oregon 97201. E-mail: wirenk{at}teleport.com

Androgen regulation of androgen receptor (AR) expression has been observed in a variety of tissues, generally as inhibition, and is thought to attenuate cellular responses to androgen. AR is expressed in osteoblasts, the bone-forming cell, suggesting direct actions of androgens on bone. Here we characterized the effect of androgen exposure on AR gene expression in human osteoblastic SaOS-2 and U-2 OS cells.

Treatment of osteoblastic cells with the nonaromatizable androgen 5-dihydrotestosterone increased AR steady state messenger RNA levels in a time- and dose-dependent fashion. Reporter assays with 2.3 kilobases of the proximal 5'-flanking region of the human AR promoter linked to the chloramphenicol acetyltransferase gene in transfected cultures showed that up-regulation of AR promoter activity by androgen was time and dose dependent. Treatment with other steroid hormones, including progesterone, 17ß-estradiol, and dexamethasone, was without effect. The antiandrogen hydroxyflutamide completely antagonized androgen up-regulation.

Thus, in contrast to many other androgen target tissues, androgen exposure increases steady state AR messenger RNA levels in osteoblasts. This regulation occurs at least partially at the level of transcription, is mediated by the 5'-promoter region of the AR gene, and is dependent on functional AR. These results suggest that physiological concentrations of androgens have significant effects on AR expression in skeletal tissue.

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