The role of androgens in the maintenance of skeletal health is manifest in the enormous increase in bone mass during adolescence in males and the association of osteoporosis with male hypogonadism. Androgens have been implicated in normal bone metabolism in females as well. Nevertheless, the mechanisms by which androgens exert effects on bone remodeling are poorly understood. The role of androgens in bone is complicated by the fact that androgen can be metabolized to estrogen in the body, and estrogen has a similar positive effect on skeletal homeostasis. However, androgen receptors are present in osteoblasts, the bone forming cell, and therefore presumably mediate most androgenic effects. We have chosen an in vitro system, that can be carefully controlled, in which to characterize the effects of androgens and androgen receptor on osteoblasts. In preliminary studies we have demonstrated that androgen receptor regulation occurs via both homologous and heterologous ligands, that progestational effects in bone may occur via interactions with the androgen receptor, and that androgens have rapid effects in osteoblasts, sensitive to protein synthesis inhibitors, suggesting the presence of labile modulatory protein(s) involved in androgenic action. The primary objective of this proposal is the elucidation of the role of the androgen receptor, and its regulation, in the mediation of androgenic effects in osteoblasts. Specific objectives include: 1) define androgen receptor regulation with the use of binding and Western analyses, measures of mRNA half-lives and transcriptional activity, and pulse-chase studies; and explore androgen receptor distribution in vitro and in vivo with immunocytochemical, in situ hybridization, and RNAase protection studies, 2) determine the role of the androgen receptor in the transduction of progestational signals in osteoblasts through the use of specific receptor antagonists, and transfection studies.
| Wiren, K; Keenan, E; Zhang, X et al. (1999) Homologous androgen receptor up-regulation in osteoblastic cells may be associated with enhanced functional androgen responsiveness. Endocrinology 140:3114-24 |
| Wiren, K M; Zhang, X; Chang, C et al. (1997) Transcriptional up-regulation of the human androgen receptor by androgen in bone cells. Endocrinology 138:2291-300 |
