Androgens regulate bone resorption activity of isolated osteoclasts in vitro

For many years it has been recognized that sex steroids have profound effec ts on bone metabolism. The current perception is that estrogen decreases bo ne resorption and androgen increases bone deposition. To investigate the po tential for androgens to directly modulate bone resorption, we have examine d avian osteoclast and human and mouse osteoclast-like cells for androgen r esponsiveness. There was a dose-dependent decrease in resorption activity i n response to alpha-dihydrotestosterone (alpha-DHT), beta-DHT, testosterone , or the synthetic androgen RU1881, This decrease was blocked by cotreatmen t with the specific androgen antagonist hydroxy-flutamide. Further examinat ion of avian osteoclasts revealed that the cells exhibited specific and sat urable nuclear binding of tritiated RU1881 and that alpha-DHT stimulated th e activity of the androgen response element as measured by using a chloramp henicol acetyltransferase reporter plasmid, In addition, avian osteoclasts responded to androgen treatment with elevated production and secretion of t ransforming growth factor beta, a well documented response to androgen expo sure in other cell systems. Treatment with either alpha-DHT or beta-DHT for 24 hours resulted in a significant dose-dependent decrease in secretion of cathepsin B and tartrate-resistant acid phosphatase. This response to beta -DHT, a stereoisomer of alpha-DHT that is inactive in other androgen recept or-dependent systems, supports the hypothesis that the osteoclast androgen receptor has unusual ligand-binding properties. Taken together, these resul ts confirm the presence of functional androgen receptors in these cells and support the conclusion that osteoclasts are able to respond directly to an drogens in vitro and thus are potential androgen target cells in vivo.