ANDROGEN RECEPTOR IN OSTEOBLASTS

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.