Studies of the Mechanism by which Androgens Enhance Mitogenesis and Differentiation in Bone Cells*

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Abstract
Recently, we reported a direct effect of androgens on murine and human bone cells to stimulate bone cell proliferation and differentiation. To test whether this effect of androgenic steroids might be mediated by growth factors, we measured relative concentrations of insulin-like growth factor-I and -II (IGF-I and IGF-II) and transforming growth factor-.beta. (TGF.beta.) in the conditioned medium from androgen-treated murine calvarial cell cultures. Only the concentration of TGF.beta. was increased. Consistent with the increased secretion of TGF.beta. in the mouse calvarial cell system, we observed an increased expression of TGF.beta. mRNA in a normal human osteoblastic cell system. We also determined whether androgens alter the response to growth factors. We found that dihydrotestosterone (DHT) treatment enhanced the mitogenic effects of fibroblast growth factor (FGF) and IGF-II but not those of IGF-I. The enhanced effect of FGF and IGF-II after DHT pretreatment was not affected by addition of TGF.beta.-blocking antibodies or by changing the culture medium. This indicated that in addition to increased release of TGF.beta., another mechanism might be involved in the action of DHT on human and murine bone cells. Thus, we investigated the binding of human IGF-II to human osteoblastic cells and observed an increase in IGF-II binding after DHT treatment. Our results are consistent with a mechanism of action of androgens on bone cells that involves the induction of TGF.beta. and, in addition, may sensitize the cells to show an enhanced response to FGF and IGF-II, possibly by changing the receptor binding of mitogenic growth factors.