Effects of androgens on the insulin-like growth factor system in an androgen-responsive human osteoblastic cell line

Although androgens have significant effects on bone metabolism, the mediato rs of their effects are still unclear. As the insulin-like growth factors ( IGFs) and IGF-binding proteins (IGFBPs) have important effects on osteoblas t proliferation and differentiation, we examined androgen effects on the IG F system in a conditionally immortalized human fetal osteoblastic cell line , hFOB/AR-6, which displays a mature osteoblastic phenotype and physiologic al levels of functional androgen receptors. The nonaromatizable androgen, 5 alpha-dihydrotestosterone (5 alpha DHT), and testosterone, but not dehydro epiandrosterone, increased IGF-I messenger RNA (mRNA) levels up to 4-fold i n a dose (10(-12)-10(-6) M)- and time (2-72 h)-dependent fashion. These cha nges were prevented by the specific androgen receptor antagonist, hydroxyfl utamide. In addition, 5 alpha-DHT decreased IGFBP-4 mRNA and protein levels by 2- and 4-fold, respectively, and increased IGFBP-2 and -3 mRNA and prot ein levels by 6- and 7-fold (for mRNA) and 3- and 5-fold (for protein), res pectively. hFOB/AR-6 cells expressed the type-IIGF receptor, but this was n ot regulated by 5 alpha DHT. 5 alpha DHT and IGFBP-3 specifically increased hFOB/AR-6 cell proliferation, and a monoclonal antibody specific for TGF-I blocked this effect. Thus, androgens increase the expression of IGF-I, IGF BP-2, and IGFBP-3, but decrease levels of the inhibitory IGFBP-4 in an andr ogen-responsive human osteoblastic cell line. Our data are consistent with the hypothesis that the effects of androgen on bone cells may be mediated a t least in part by increases in IGF-I production and by differential regula tion of IGFBPs.