The relative importance of sex steroid receptors for bone metabolism

Abstract

Estrogen deficiency increases the risk of a wide variety of pathological conditions including osteoporosis. Morbidity from osteoporosis is substantial in both men and women. Hormone replacement therapy (HRT, including estrogens) is associated with side-effects such as increased risk of breast cancer, stroke and deep venous thrombosis, and agents that can maintain the benefit of estrogen but avoid the risks are therefore needed. Testosterone is the precursor molecule of estradiol and its effects are mediated either via a direct activation of the androgen receptor (AR) or indirectly via aromatisation into estradiol and activation of estrogen receptor alpha (ERalpha) or ERbeta. The aim of this thesis was to compare the relative importance of and the interactions among AR, ERalpa, and ERbeta for bone metabolism in male and female mice. Male mice Orchidectomy resulted in a pronounced decrease in trabecular bone mineral density (BMD), which was completely prevented by estrogen treatment in wild type (WT) and ERbeta-/- but not in ERalpha-/- or ERalpha-/-beta-/- mice. This finding demonstrates that ERalpha is important while ERbeta is of no importance for the regulation of the trabecular BMD in male mice. Furthermore, in an additional study we showed that not only ERalpha activation but also a specific AR activation preserves the amount of trabecular bone in orchidectomized mice. Micro-computer tomography analyses demonstrated that ERalpha activation resulted in both preserved thickness and number of trabeculae, whereas AR activation only preserved the number but not the thickness of trabeculae. ERalpha activation increased serum levels of insulin-like growth factor I, which were positively correlated with all the cortical and trabecular bone parameters specifically preserved by ERalpha activation, suggesting that insulin-like growth factor I might mediate these skeletal effects of ERalpha activation. Thus, the in vivo bone-sparing effect of ERalpha activation is distinct from the bone-sparing effect of AR activation in adult male mice.Female mice By demonstrating that combined ER and AR activation resulted in a more pronounced effect on the trabecular bone than the single treatments in ovariectomized mice, we extended our previous findings that ERalpha, ERbeta as well as AR are of importance for the trabecular bone in female mice. Because the ER and the AR pathways are distinct from each other, a combined treatment of selective ER modulators and selective AR modulators might be beneficial in the treatment of osteoporosis. By investigating global estrogen-regulated gene transcription in ovariectomized mice, we found that ERbeta inhibits ERalpha-mediated gene transcription in the presence of ERalpha, whereas in the absence of ERalpha ERbeta can partially replace ERalpha. These findings indicate that one important physiological role of ERbeta is to modulate ERalpha-mediated gene transcription, supporting a "Yin Yang" relationship between ERalpha and ERbeta in mice.In conclusion, ERalpha and AR-activation increases the amount of trabecular bone by distinct mechanisms while ERbeta is of no importance for the trabecular bone in male mice. In female mice, AR and ER-activation results in an additive effect on trabecular bone mass and ERbeta modulates ERalpha-mediated gene transcription in bone.