Farman H H, Windahl S H, Westberg L, Isaksson H, Egecioglu E, Schele E, Ryberg H, Jansson J O, Tuukkanen J, Koskela A, Xie S K, Hahner L, Zehr J, Clegg D J, Lagerquist M K, Ohlsson C
Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Endocrinology. 2016 Aug;157(8):3242-52. doi: 10.1210/en.2016-1181. Epub 2016 Jun 2.
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.
雌激素是骨量的重要调节因子，其作用主要通过雌激素受体（ER）α介导。中枢ERα对骨量发挥抑制作用。ERα在下丘脑的弓状核（ARC）和腹内侧核（VMN）中高度表达。为了检测位于ARC的促黑素细胞皮质激素（POMC）神经元中的ERα是否参与骨量调节，我们使用了特异性缺乏POMC神经元中ERα表达的小鼠（POMC-ERα(-/-)）。将雌性POMC-ERα(-/-)小鼠和对照小鼠进行卵巢切除（OVX），并用溶剂或雌二醇（0.5μg/d）处理6周。正如预期的那样，雌二醇处理增加了OVX对照小鼠股骨的皮质骨厚度、胫骨的皮质骨机械强度以及股骨和椎骨的小梁骨体积分数。重要的是，与OVX对照小鼠相比，OVX POMC-ERα(-/-)小鼠的雌激素反应在皮质骨厚度（增加126±34%，P<.01）和机械强度（增加193±38%，P<.01）方面显著增强。为了检测VMN中的ERα是否参与骨量调节，使用腺相关病毒载体使ERα沉默。下丘脑VMN中ERα的沉默导致骨量不变。总之،缺乏POMC神经元中ERα的小鼠对皮质骨量和机械强度表现出增强的雌激素反应。我们认为，ARC下丘脑POMC神经元中中枢ERα活性的抑制作用与骨中刺激性外周ERα介导的作用之间的平衡决定了雌性小鼠的皮质骨量。
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