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

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.

Androgen effects on bone metabolism: recent progress and controversies

“…TIEG has been recognized as a transcription factor, that mediates some effects of TGF-b (129,130). Of interest, the decrease in TGF-b and TIEG mRNA levels paralleled growth inhibition of 5a-DHT in this cell line (44), indicating that TGF-b may indeed mediate the effects of androgens on osteoblast proliferation (44,126).…”

“…Estrogen is known to stimulate both de novo synthesis of TGF-b and activation of latent TGF-b (110,122,125). Several groups have demonstrated that androgens (5a-DHT, testosterone, and DHEA) increase TGF-b gene expression (31,126) and activity (127), suggesting that at least part of the positive effects of androgens may be mediated by an osteoblast-derived increase in TGF-b production and activity. In support of this hypothesis are the findings of an in vivo study conducted on male rats (128).…”

“…Rodent bone cells differ from human bone cells in the high abundance of IGF-I and an altered IGFBP profile (131). While some studies have found that the mRNA levels of IGF-I and IGF-II by osteoblastic (126,135) and preosteoblastic cells (33) were not affected by androgen treatment, Gori et al (136) have demonstrated that, in the hFOB/AR-6 cell line, IGF-I mRNA levels were upregulated sixfold by 5a-DHT. Thus, at least part of the anabolic effect of androgens on bone may be due to increased IGF-I production by osteoblasts (133,134).…”

Age-Related Changes of Bone Mineral Density and Microarchitecture in Miniature Pigs

“…Moreover, McCormick et al reported that early onset of puberty in females was related to differences in BMD values between the sexes during puberty [25]. It was recently shown that sex steroids have receptors and exert biologic effects on both epiphyseal cartilage cells [1,7] and bone cells [5,21]. In these studies, it was suggested that these hormones play an important role in skeletal growth and mineralization.…”

Testosterone mediates satellite cell activation in denervated rat levator ani muscle

“…Evidence for such interaction exists in other androgensensitive systems with regard to receptors for epidermal growth factor (prostate; Mulder et al, 1989) and transforming growth factor (bone; Kasperk et al, 1990). More recently, the expression of hepatocyte growth factor/scatter factor (HGF/SF) has been demonstrated in osteoblasts (Blanquaert et al, 1999), stromal cells of mouse prostate (Sasaki and Enami, 1999) and myoid cells of rat testis (Catizoni et al, 1999).…”