Gonadal and adrenal androgens are potent regulators of human bone cell metabolism in vitro

Androgens stimulate bone formation and play an important role in the maintenance of bone mass, Clinical observations suggest that both gonadal and adrenal androgens contribute to the positive impact of androgenic steroids on bone metabolism, We investigated the mechanism of action of the adrenal androgen dehydroepiandro-sterone (DHEA) and its sulfated compound dehydroepiandrosterone sulfate (DHEAS) on human osteoblastic cells (HOCs) in vitro, The DHEA- and DHEAS-induced effects were analyzed in parallel with the: actions elicited by the gonadal androgen dihydrotestosterone (DHT), There was no qualitative difference between the effects of gonadal and adrenal androgens on HOC metabolism in vitro, Both were stimulatory as regards cell proliferation and differentiated functions, but the gonadal androgen DHT was significantly more potent than DHEA. The actions of DHT and DHEA on HOC proliferation and alkaline phosphatase (ALP) production could be prevented by the androgen receptor antagonist hydroxyflutamide and inhibitory transforming growth factor beta antibodies (TGF-beta ab), respectively, but were not affected by the presence of the 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) and 5-alpha-reductase (5-AR) inhibitor 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza-5 alpha-androstan-3-one (4-MA). This indicates that DHT and DHEA (1) exert their mitogenic effects by androgen receptor-mediated mechanisms, (2) stimulate ALP production by increased TGF-beta expression, (3) that the action of DHT is not affected by the presence of 4-MA, and that (4) DHEA does not need to be metabolized by 3 beta HSD or 5-AR first to exert its effects on HOCs in vitro.