Bone Abstracts (2016) 5 HTHT2 | DOI: 10.1530/boneabs.5.HT2

Mice lacking estrogen receptor [alpha] in hypothalamic POMC neurons display enhanced estrogenic response on cortical bone mass

Helen Farman1, Sara Windahl1, Deborah Clegg2, Shang Kui Xie2, Lars Westberg3, Hanna Isaksson4,5, Emil Egecioglu3, Erik Schele6, John Olov Johnsson6, Juha Tuukkanen7, Lisa Hahner2, Jordan Zehr2, Marie Lagerquist1 & Claes Ohlsson1

1Medicine, Gothenburg, Sweden; 2Internal Medicine, Dallas, Texas, USA; 3Neuroscience and Physiology, Gothenburg, Sweden; 4Biomedical Engineering, Lund, Sweden; 5Clinical Sciences, Lund, Sweden; 6Neuroscience and Physiology/Endocrinology, Gothenburg, Sweden; 7Anatomy and Cell Biology, Oulu, Finland.

Estrogens are important regulators of bone mass and exert their physiological effects on bone mainly via estrogen receptor α (ERα). Central ERα has been reported to exert an inhibitory role on bone mass. ERα is widely distributed in the brain with a high expression in the arcuate nucleus (ARC) and the ventral medial nucleus (VMN) in the hypothalamus. Here, we tested the hypothesis that ERα in hypothalamic pro-opiomelanocortin (POMC) neurons, located in (ARC), is involved in the regulation of bone mass.

Six-month-old female POMC-ERα−/− and control mice were ovariectomized (ovx) and treated with either vehicle or estradiol (E2; 0.5 μg/day) for 6 weeks. As expected, E2-treatment increased the cortical bone thickness in the diaphyseal region of femur, the cortical bone mechanical strength in tibia (Max load at failure) and the trabecular bone volume fraction (BV/TV) in both the distal metaphyseal region of femur and vertebrae L5 in ovx control mice. Importantly, for cortical bone thickness (+126±34%, P<0.001) and mechanical strength (Max load at failure; +193±38%, P<0.001), the estrogenic responses were substantially increased in ovx POMC ERα−/− mice compared with the estrogenic responses in ovx control mice. In contrast, the estrogenic response on trabecular bone volume fraction was unchanged in the vertebrae L5 and only modestly augmented in the distal metaphyseal region of femur in POMC-ERα−/− mice.

In a separate experiment, ERα in hypothalamic VMN was silenced using an adeno-associated viral vector, resulting in unchanged bone mass.

In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We 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.