In vitro studies

Growth and resorption of bone tissue are mediated by osteoblasts and osteoclasts, respectively. Both types of cells exert mutual influence on each other and equilibrium between the activity ofboth cell lines maintains net bone mass during constant renewal and turnover, while decreased osteoblast activity as well as enhanced osteoclast activity will result in loss of bone mass. Androgen receptors have been located on normal human osteoblasts (Colvard et al. 1989) and both aromatizable and non-aromatizable androgens can stimulate human osteoblast proliferation in vitro (Kasperk etal. 1997), a process that requires adequate storage ofvitamin D (Somjen etal. 1989).

Bone deformation strain represents a stimulus for osteoblastic activity. Andro-gens modify the effects induced by the mechanoperception of human osteoblastic cells by affecting adhesion molecule expression, i.e. fibronectin and the fibronectin receptor. These substances facilitate the adhesion of bone cells to the extracellular matrix, which represents a crucial requirement for osteoblastic development and function (Liegibel etal. 2002). In addition, osteoprotegerin secretion, which is unaffected by mechanical strain alone, is doubled when this stimulus occurs in the presence of androgens. Osteoprotegerin represents a decoy receptor for RANKL (receptor activator of nuclear factor-kappaB ligand). RANKL is secreted by osteoblasts; it induces osteoclastogenesis and stimulates osteoclast differentation (Khosla 2001). Thus, osteoprotegerin inhibits bone resorptive effects induced by RANKL (Liegibel etal. 2002). Accordingly, testosterone levels are positively associated with osteoprotegerin concentrations in cross-sectional approaches in healthy men (Szulc et al. 2001). In contrast, dihydrotestosterone has been reported to decrease osteoprotegerin mRNA expression in a fetal human osteoblastic cell line (Hofbauer et al. 2002). Testosterone also directly inhibits shedding of RANKL by osteoblasts (Huber et al. 2001); similarly, androgen receptor knock-out mice exhibit an upregulation of RANKL production (Kawano et al. 2003).

Local action of cytokines such as interleukins 1 and 6 (IL-1 and IL-6) plays an important role in bone metabolism. Both substances induce bone resorption by promotion of osteoclast activation and diffentiation. Androgens inhibit expression of the IL-6 gene in marrow-derived stromal cells, an effect requiring the androgen receptor (Bellido et al. 1995, Hofbauer et al. 1999). Similar effects were observed concerning IL-1 expression (Pilbeam and Raisz 1990). Latter effect seems to be age-dependent and is mitigated in cell cultures from older mice (Wang et al. 1999).

Parathyroid hormone (PTH) induces osteoclast formation and differentiation. Androgens have a direct inhibiting effect on this process via osteoclasts, which express androgen receptors: these cells are also blocked from PTH effects by androgens when no conversion to estrogens occurs (Chen etal. 2001). In addition, PTH-stimulated accumulation of cAMP in osteoblasts can also be mitigated by androgens (Fukayama and Tashijian 1989).

The direct impact of androgens on osteoclasts has not been fully resolved. A direct effect on resorption activities of osteoclasts has been reported: an inhibition of osteoclastic functions was seen in response to testosterone and dihydrotestos-terone; this could be blocked by the androgen receptor antagonist flutamide. Interestingly, also (3-DHT, a stereoisomer of a-DHT, that is inactive in other androgen receptor-dependent systems, can achieve androgen effects, which supports the hypothesis that the osteoclast androgen receptor has unusual ligand-binding properties (Pederson et al. 1999). In contrast, resorption pits produced by cultured primary osteoclasts from androgen receptor knock-out mice seemed normal both in terms of numbers and area when compared with osteoclasts from wild-type (WT)-littermates (Kawano etal. 2003).

It is possible that some of these effects are due to non-genotropic action of activated androgen receptors. There are indications that a non-specific activation of the ligand binding domain of the androgen receptor both by androgenic and estrogenic compounds can induce anti-apoptotic effects in osteoblasts and increase apoptosis in osteoclasts. This effect seems to be dissociated from transcriptional activity (Kousteni et al. 2001; 2003). Corresponding effects were seen in a mouse model (see 7.2.2).

Thus, androgens decrease the number of bone remodeling cycles by modifying the genesis of osteoclasts and osteoblasts from their respective progenitor cells. In addition, androgens also exert effects on the lifespan of mature bone cells: they exert pro-apoptotic effects on osteoclasts and anti-apoptotic effects on osteoblasts and osteocytes. Testosterone also modulates effects induced by other hormones and cytokines involved in bone metabolism. For a summary see Fig. 7.1.

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