CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons
CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons
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DOI：
10.1101/gad.1977210
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发表时间：
2010-10-15
影响因子：
10.5
通讯作者：
Karsenty, Gerard
中科院分区：
文献类型：
--
作者：
Oury, Franck;Yadav, Vijay K.;Karsenty, Gerard
5-羟色胺是一种生物胺，根据其合成部位的不同，调节骨量增加的方式也不同。它在肠道中合成时会减少应收量，在大脑中合成时会增加。肠源性5-羟色胺一旦与成骨细胞上存在的Htr1b受体结合，就会引发信号转导事件，并最终通过cAMP反应元件结合蛋白(CREB)调节成骨细胞的增殖。相反，我们不知道脑源性5-羟色胺与下丘脑腹内侧核(VMH)神经元上的Htr2c受体结合后如何促进骨量增加。通过基因表达分析，5-羟色胺处理野生型和Htr2c(-/-)下丘脑外植体，以及小鼠细胞特异性基因缺失，我们发现，在与VMH神经元上的Htr2c受体结合后，5-羟色胺使用钙调蛋白激酶(CaMK)依赖的信号级联，涉及CaMKKβ和CaMKIV，以降低交感神经张力，增加骨量增加。我们进一步表明，这些事件的转录中介是CREB，在下丘脑外植体处理5-羟色胺后，其在Ser133上的磷酸化被CaMKIV增加。一项微阵列实验确定了两个交感活性最佳所必需的基因，它们的表达受到CREB的调控。这些结果提供了对下丘脑神经元中5-羟色胺信号如何调节骨量增加的分子理解，并确认CREB是这一功能的关键决定因素，尽管其表达的机制取决于细胞类型、神经元或成骨细胞。
Serotonin is a bioamine regulating bone mass accrual differently depending on its site of synthesis. It decreases accrual when synthesized in the gut, and increases it when synthesized in the brain. The signal transduction events elicited by gut-derived serotonin once it binds to the Htr1b receptor present on osteoblasts have been identified and culminate in cAMP response element-binding protein (CREB) regulation of osteoblast proliferation. In contrast, we do not know how brain-derived serotonin favors bone mass accrual following its binding to the Htr2c receptor on neurons of the hypothalamic ventromedial nucleus (VMH). We show here-through gene expression analysis, serotonin treatment of wild-type and Htr2c(-/-) hypothalamic explants, and cell-specific gene deletion in the mouse-that, following its binding to the Htr2c receptor on VMH neurons, serotonin uses a calmodulin kinase (CaMK)-dependent signaling cascade involving CaMKK beta and CaMKIV to decrease the sympathetic tone and increase bone mass accrual. We further show that the transcriptional mediator of these events is CREB, whose phosphorylation on Ser 133 is increased by CaMKIV following serotonin treatment of hypothalamic explants. A microarray experiment identified two genes necessary for optimum sympathetic activity whose expression is regulated by CREB. These results provide a molecular understanding of how serotonin signals in hypothalamic neurons to regulate bone mass accrual and identify CREB as a critical determinant of this function, although through different mechanisms depending on the cell type, neuron, or osteoblast in which it is expressed.