TRANSCRIPTIONAL UP-REGULATION OF THE HUMAN ANDROGEN RECEPTOR BY ANDROGEN IN BONE-CELLS

Androgen regulation of androgen receptor (AR) expression has been obse rved in a variety of tissues, generally as inhibition, and is thought to attenuate cellular responses to androgen. AR is expressed in osteob lasts, the bone-forming cell, suggesting direct actions of androgens o n bone. Here we characterized the effect of androgen exposure on AR ge ne expression in human osteoblastic SaOS-2 and U-2 OS cells. Treatment of osteoblastic cells with the nonaromatizable androgen 5 alpha-dihyd rotestosterone increased AR steady state messenger RNA levels in a tim e- and dose-dependent fashion. Reporter assays with 2.3 kilobases of t he 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 do se dependent. Treatment with other steroid hormones, including progest erone, 17 beta-estradiol, and dexamethasone, was without effect. The a ntiandrogen hydroxyflutamide completely antagonized androgen up-regula tion. Thus, in contrast to many other androgen target tissues, androge n exposure increases steady state AR messenger RNA levels in osteoblas ts. This regulation occurs at least partially at the level of transcri ption,is mediated by the 5'-promoter region of the AR gene, and is dep endent on functional AR. These results suggest that physiological conc entrations of androgens have significant effects on AR expression in s keletal tissue.