Although androgens have significant effects on bone metabolism, the mediators of their effects are still unclear. As the insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have important effects on osteoblast proliferation and differentiation, we examined androgen effects on the IGF system in a conditionally immortalized human fetal osteoblastic cell line, hFOB/AR-6, which displays a mature osteoblastic phenotype and physiological levels of functional androgen receptors. The nonaromatizable androgen, 5α-dihydrotestosterone (5αDHT), and testosterone, but not dehydroepi-androsterone, increased IGF-I messenger RNA (mRNA) levels up to 4-fold in a dose (10-12-10-6 M)- and time (2-72 h)-dependent fashion. These changes were prevented by the specific androgen receptor antagonist, hydroxyflutamide. In addition, 5α-DHT decreased IGFBP-4mRNA and protein levels by 2- and 4-fold, respectively, and increased IGFBP-2 and -3 mRNA and protein levels by 6- and 7-fold (for mRNA) and 3- and 5-fold (for protein), respectively, hFOB/AR-6 cells expressed the type-I IGF receptor, but this was not regulated by 5αDHT. 5αDHT and IGFBP-3 specifically increased hFOB/AR-6 cell proliferation, and a monoclonal antibody specific for IGF-I blocked this effect. Thus, androgens increase the expression of IGF-I, IGFBP-2, and IGFBP-3, but decrease levels of the inhibitory IGFBP-4 in an androgen-responsive human osteoblastic cell line. Our data are consistent with the hypothesis that the effects of androgen on bone cells may be mediated at least in part by increases in IGF-I production and by differential regulation of IGFBPs.
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