Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass.
Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass.
复制标题
DOI：
10.1210/en.2016-1181
复制
发表时间：
2016-08
期刊：
影响因子：
4.8
通讯作者：
Ohlsson C
中科院分区：
文献类型：
--
作者：
Farman HH;Windahl SH;Westberg L;Isaksson H;Egecioglu E;Schele E;Ryberg H;Jansson JO;Tuukkanen J;Koskela A;Xie SK;Hahner L;Zehr J;Clegg DJ;Lagerquist MK;Ohlsson C
雌激素是重要的骨量调节因子，其作用主要通过雌激素受体（ER）α介导。中枢ERα对骨量有抑制作用。ERα在下丘脑弓状核（ARC）和腹内侧核（VMN）高表达。为了测试位于ARC中的前阿黑皮素（POMC）神经元中的ERα是否参与骨量的调节，我们使用了POMC神经元中特异性缺乏ERα表达的小鼠（POMC-ERα−/−）。对雌性POMC-ERα−/−和对照小鼠进行卵巢切除（OVX），并用溶剂或雌二醇（0.5 μg/d）处理6周。正如预期的那样，雌二醇治疗增加了OVX对照小鼠股骨中的皮质骨厚度、胫骨中的皮质骨机械强度以及股骨和椎骨中的松质骨体积分数。重要的是，与OVX对照小鼠的皮质骨厚度（+126 ± 34%，P < .01）和机械强度（+193 ± 38%，P <.01）的雌激素反应相比，OVX POMC-ERα−/−小鼠的雌激素反应显著增加。为了测试VMN中的ERα是否参与骨量的调节，使用腺相关病毒载体沉默ERα。下丘脑VMN中ERα的沉默导致骨量不变。总之，POMC神经元中缺乏ERα的小鼠表现出增强的皮质骨质量和机械强度的雌激素反应。我们认为，ARC中下丘脑POMC神经元的中枢ERα活性抑制作用和骨骼中刺激性外周ERα介导的作用之间的平衡决定了雌性小鼠的皮质骨质量。
Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα−/−). Female POMC-ERα−/− and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα−/− mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted 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 in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.