The Role of Estrogen Receptor α Signaling in the Regulation of Bone Mass

Estrogens are major regulators of skeletal growth and maintenance in both females and males. Estrogen receptor α (ERα) is the main mediator of estrogenic effects in bone. Thus, estrogen signaling via ERα is a target for treatment of estrogen-related bone diseases including osteoporosis. However, treatment with estrogen leads to side effects in both genders. The aim of this thesis was to characterize different ERα signaling pathways in order to increase the knowledge regarding the mechanisms behind the protective effects of estrogen on bone mass versus adverse effects in other organs.\nWe have evaluated the role of ERα expression in two distinct hypothalamic nuclei. Female mice lacking ERα expression in proopiomelanocortin (POMC) neurons, mainly found in the arcuate nucleus, displayed substantially enhanced estrogenic response on cortical bone mass while lack of ERα in the ventromedial nucleus revealed no effects on bone mass. We therefore propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.\nWe have also evaluated the role of ERα signaling pathways in males. We found that the ERα activation function (AF)-2 was required for the estrogenic effects on all evaluated parameters. In contrast, the role of ERαAF-1 was tissue specific, where trabecular bone was dependent on ERαAF-1, while effects on cortical bone did not require ERαAF-1. In addition, all evaluated effects of the selective estrogen receptor modulators (SERMs) were dependent on a functional ERαAF-1.\nIn addition to nucleus, ERα is also located at the plasma membrane, where it can initiate extra-nuclear signaling. We found that extra-nuclear ERα signaling affects cortical bone mass in males and that this effect is dependent on a functional ERαAF-1. To further determine the role of membrane-initiated ERα signaling, we used a mouse model lacking an ERα palmitoylation site, which is crucial for membrane localization of ERα. We showed that membrane ERα signaling is essential for normal development and maintenance of trabecular and cortical bone, and is crucial for normal estrogen response in both trabecular and cortical bone in male mice.\nThe studies presented in this thesis have increased our knowledge regarding estrogen signaling pathways in both females and males and may contribute to the design of new, bone-specific treatment strategies that maintain the protective effects of estrogen but minimize the adverse effects.