Estrogen receptor-α expression in neuronal cells affects bone mass
Estrogen receptor-α expression in neuronal cells affects bone mass
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DOI：
10.1073/pnas.1111436109
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发表时间：
2012-01-17
影响因子：
11.1
通讯作者：
Lagerquist, Marie K.
中科院分区：
文献类型：
--
作者：
Ohlsson, Claes;Engdahl, Cecilia;Lagerquist, Marie K.
一般认为，骨量是由内分泌机制和局部骨环境控制的。最近的研究表明，中枢通路参与调节骨量。雌激素参与骨稳态的调节，CNS也是雌激素作用的靶点。本研究的目的是研究在体内的作用，中央雌激素受体α（ER α）表达的骨量。Nestin-Cre小鼠与ER α（flox）小鼠杂交，产生神经组织特异性ER α表达缺失的小鼠（nestin-ER α（-/-））。与对照组相比，nestin-ER α（-/-）小鼠的骨小梁和皮质骨区室的骨矿物质密度增加。nestin-ER α（-/-）小鼠的股骨强度增加，表现为刚度增加和最大失效载荷。nestin-ER α（-/-）小鼠的高骨量表型主要由骨形成增加引起。血清瘦素水平升高是由于白色脂肪组织（WAT）中瘦素表达增加和nestin-ER α（-/-）小鼠中WAT量略微增加的结果。瘦素受体mRNA水平在下丘脑中降低，但在骨中不降低。总之，中枢ER α信号转导的失活导致骨量增加，表明外周刺激性和中枢抑制性ER α作用之间的平衡对于骨量调节很重要。我们认为nestin-ER α（-/-）小鼠骨量增加是通过降低中枢瘦素敏感性介导的，从而增加WAT中瘦素的分泌，这反过来又导致外周瘦素诱导的骨形成增加。
It has generally been assumed that bone mass is controlled by endocrine mechanisms and the local bone environment. Recent findings demonstrate that central pathways are involved in the regulation of bone mass. Estrogen is involved in the regulation of bone homeostasis and the CNS is also a target for estrogen actions. The aim of this study was to investigate in vivo the role of central estrogen receptor-alpha (ER alpha) expression for bone mass. Nestin-Cre mice were crossedwith ER alpha(flox) mice to generate mice lacking ER alpha expression specifically in nervous tissue (nestin-ER alpha(-/-)). Bone mineral density was increased in both the trabecular and cortical bone compartments in nestin-ER alpha(-/-) mice compared with controls. Femoral bone strength was increased in nestin-ER alpha(-/-) mice, as demonstrated by increased stiffness and maximal load of failure. The high bone mass phenotype in nestin-ER alpha(-/-) mice was mainly caused by increased bone formation. Serum leptin levels were elevated as a result of increased leptin expression in white adipose tissue (WAT) and slightly increased amount of WAT in nestin-ER alpha(-/-) mice. Leptin receptor mRNA levels were reduced in the hypothalamus but not in bone. In conclusion, inactivation of central ER alpha signaling results in increased bone mass, demonstrating that the balance between peripheral stimulatory and central inhibitory ER alpha actions is important for the regulation of bone mass. We propose that the increased bone mass in nestin-ER alpha(-/-) mice is mediated via decreased central leptin sensitivity and thereby increased secretion of leptin fromWAT, which, in turn, results in increased peripheral leptin-induced bone formation.