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Homologous Androgen Receptor Up-Regulation in Osteoblastic Cells May Be Associated with Enhanced Functional Androgen Responsiveness¹

Bone and Mineral Research Unit, Veterans Affairs Medical Center, (K.M.W., X.Z., E.S.O.) Portland, Oregon 97201; and the Departments of Behavioral Neuroscience (K.M.W.), Cell and Developmental Biology (K.M.W.), Medicine (K.M.W. and E.S.O.), and Physiology and Pharmacology (E.K and B.R.), Oregon Health Sciences University, Portland, Oregon 97201

Address all correspondence and requests for reprints to: Dr. Kristine Wiren, Portland VA Medical Center P3R&D39, 3710 SW Veterans Hospital Road, Portland, Oregon 97201. E-mail: wirenk{at}ohsu.edu

Although androgens have myriad effects on the skeleton, the regulation of androgen action in bone is not well understood. Androgen receptors (ARs) are known to play an important role in mediating androgen action. We have examined the effects of androgens and other sex steroids on AR levels in osteoblastic cells in vitro using two clonal human cell lines, SaOS-2 and U-2 OS. AR protein levels were quantitated both by specific androgen binding studies and Western analyses, and AR messenger RNA was measured with RNase protection assays. Potential changes in AR functionality was assessed by reporter assays.

Treatment of osteoblastic cells with the nonaromatizable androgen 5-dihydrotestosterone (DHT) increased specific androgen binding 2- to 4-fold. Similar increases in AR protein levels were documented by Western analysis in both cell lines. The androgen-mediated increase in receptor levels was time and dose dependent as well as androgen specific. Steady-state AR messenger RNA levels were also increased by DHT. When AR concentrations in osteoblastic cells were elevated with exogenous receptor, there was an enhancement of DHT responsiveness, measured by increased trans-activation of an androgen-responsive promoter.

Thus, androgen exposure increased androgen receptor protein levels and specific androgen binding in osteoblastic cells. Androgen action as measured by androgen-mediated transcriptional activation is enhanced in the presence of elevated AR levels. Consequently, these studies have revealed an additional means by which androgens may modulate skeletal metabolism.

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