Estrogen receptors in the regulation of the skeleton

Abstract: Estrogen is important for the regulation of bone growth as well as for adult bone metabolism in females. Androgens have long been considered the main sex steroid in the regulation of the skeleton in males. However, since androgens can be converted into estrogens via aromatization, the question has arisen whether estrogen also might be of importance in the regulation of the male skeleton. There are two known estrogen receptors, ERa and ERb, which can mediate the effects of estrogen. The aim of the studies in this thesis was to investigate the relative roles of the two estrogen receptor subtypes in the regulation of the skeleton in both females and males. The relative importance of ERa and ERb was studied using knock-out mice lacking either ERa, ERb, or both ERa and ERb. Studies of young female mice demonstrated that ER stimulates, while ERb represses bone growth in females. ERb was also found to repress global ERb-mediated gene transcription in bone tissue, supporting a "ying yang" relationship between ERa and ERb in female mice. It was shown that ERa is the main receptor responsible for the bone-sparing effects of estrogen on trabecular bone after ovariectomy in female mice. In addition, using DNA Microarray we identified three novel estrogen-regulated genes, which were highly correlated with trabecular bone mass and therefore probable candidate genes for the bone-sparing effects of estrogen. The studies on male mice in this thesis clearly showed that estrogen is of importance for the regulation of the male skeleton and the receptor that mediates the effects of estrogen is ERa, while ERb is of no importance. It was also demonstrated that both ERa and the androgen receptor are important for the maintenance of trabecular bone mass in adult male mice.In conclusion, this thesis has increased our knowledge about the estrogen receptor specificity in the regulation of the skeleton in both females and males and may contribute in the search for subtype specific drugs that maintain the benefits of estrogen but minimize the risks.