Bone Abstracts (2016) 5 OC6.4 | DOI: 10.1530/boneabs.5.OC6.4

Extranuclear effects of estrogen on cortical bone in males is dependent on estrogen receptor A activation function-1

Helen Farman1, Jianyao Wu1, Karin Gustafsson1, Sara Windahl1, Sung Kim2, John Katzenellenbogen2, Claes Ohlsson1 & Marie Lagerquist1

1Center for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 2Department of Chemistry, University of Illinois, Urbana, USA.

Estradiol (E2) signaling via estrogen receptor alpha (ERα) is important for the male skeleton as demonstrated by ERα inactivation in both mice and man. ERα mediates estrogenic effects by translocating to the nucleus and there affects gene transcription, but some effects can also be mediated via extra-nuclear actions of the receptor by, e.g., triggering cytoplasmic signaling cascades. ERα contains various domains and the role of activation function 1 (ERαAF-1) is known to be tissue-specific. The aim of this study was to determine the importance of extra-nuclear estrogen action for maintaining the skeleton in males and to determine the role of ERαAF-1 for mediating these effects. 5-month-old male wild type (WT) and ERαAF-1 inactivated (ERαAF-10) mice were orchidectomized (orx) and treated with equimolar doses of 17β-E2 or 17β-E2 dendrimer conjugate (EDC), which is incapable of entering the nucleus and thereby only stimulates extra-nuclear ER actions, or their corresponding vehicles for 3.5 weeks. Tibias were analyzed using pQCT. As expected, E2 treatment increased cortical thickness (+26%, P<0.001) and trabecular BMD (+112%, P<0.001) in WT mice compared to vehicle treatment. Treatment with EDC resulted in increased cortical thickness in WT mice (+7%, P<0.05), while no effect of EDC was detected in the trabecular bone compartment. E2 treatment increased cortical thickness (+8%, P<0.05), but had no effect on trabecular bone in ERαAF-10 mice. Interestingly, the effect of EDC on cortical bone was abolished in mice lacking a functional ERαAF-1 domain. In conclusion, extra-nuclear estrogenic signaling is able to enhance cortical bone mass in males and this effect is dependent on a functional ERαAF-1.

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