The role of activation functions 1 and 2 of estrogen receptor-α for the effects of estradiol and selective estrogen receptor modulators in male mice

Anna Borjesson, Helen H Farman, Cecilia Engdahl, Antti Koskela, Klara Sjogren, Jenny M Kindblom, Alexandra Stubelius, Ulrika Islander, Hans Carlsten, Maria C Antal, Andree Krust, Pierre Chambon, Juha Tuukkanen, Marie K Lagerquist, Sara H Windahl, Claes Ohlsson

Research output: Contribution to journalArticlepeer-review

Abstract

Estradiol (E2) is important for male skeletal health and the effect of E2 is mediated via estrogen receptor (ER)-α. This was demonstrated by the findings that men with an inactivating mutation in aromatase or a nonfunctional ERa had osteopenia and continued longitudinal growth after sexual maturation. The aim of the present study was to evaluate the role of different domains of ERa for the effects of E2 and selective estrogen receptor modulators (SERMs) on bone mass in males. Three mouse models lacking either ERαAF-1 (ERαAF-10), ERαAF-
2 (ERαAF-20), or the total ERα (ERα-/-) were orchidectomized (orx) and treated with E2 or placebo. E2 treatment increased the trabecular and cortical bone mass and bone strength, whereas it reduced the thymus weight and bone marrow cellularity in orx wild type (WT) mice. These parameters did not respond to E2 treatment in orx ERα-/- or ERαAF-20 mice. However, the effects of E2 in orx ERαAF-10 mice were tissue-dependent, with a clear response in cortical bone parameters and bone marrow cellularity, but no response in trabecular
bone. To determine the role of ERαAF-1 for the effects of SERMs, we treated orx WT and ERαAF-10 mice with raloxifene (Ral), lasofoxifene (Las), bazedoxifene (Bza), or vehicle. These SERMs increased total body areal bone mineral density (BMD) and trabecular volumetric BMD to a similar extent in orx WT mice. Furthermore, only Las increased cortical thickness significantly and only Bza increased bone strength significantly. However, all SERMs showed a tendency toward increased cortical bone parameters. Importantly, all SERM effects were
absent in the orx ERαAF-10 mice. In conclusion, ERαAF-2 is required for the estrogenic effects on all evaluated parameters, whereas the role of ERαAF-1 is tissue-specific. All evaluated effects of Ral, Las and Bza are dependent on a functional ERαAF-1. Our findings might contribute to the development of bone-specific SERMs in males.
Original languageEnglish
Pages (from-to)1117-1126
Number of pages10
JournalJournal of Bone and Mineral Research
Volume28
Issue number5
DOIs
Publication statusPublished - May 2013

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