Central control of bone remodeling by neuromedin U
Central control of bone remodeling by neuromedin U
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DOI：
10.1038/nm1640
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发表时间：
2007-10-01
期刊：
影响因子：
82.9
通讯作者：
Takeda, Shu
中科院分区：
文献类型：
--
作者：
Sato, Shingo;Hanada, Reiko;Takeda, Shu
骨质疏松症是最常见的骨骼疾病，其骨重塑包括两个阶段：生成基质的成骨细胞形成骨(1)和破骨细胞吸收骨(2)。厌氧性激素瘦素（3-5）通过下丘脑接力抑制骨形成（6,7），这表明影响下丘脑能量代谢的其他分子也可以调节骨量。Neuromedin U （NMU）是一种厌氧性神经肽，通过不明确的机制独立于瘦素起作用（8,9）。在这里，我们发现Nmu（-/-）缺陷小鼠由于骨形成增加而具有高骨量；这在雄性小鼠中比雌性小鼠更明显。生理和基于细胞的实验表明，NMU作用于中枢神经系统，而不是直接作用于骨细胞，以调节骨重塑。值得注意的是，瘦素或交感神经系统介导的骨形成抑制在Nmu（-/-）小鼠中被消除（6,7），这表明分子钟基因（瘦素抑制骨形成的介质）的骨表达发生了改变。此外，用天然的NMU受体激动剂治疗野生型小鼠可减少骨量。总的来说，这些结果表明NMU可能是迄今为止确定的瘦素依赖性骨量调节的第一个中枢介质。考虑到NMU作用的抑制剂和激活剂的存在（10），我们的研究结果可能会影响骨质疏松症等低骨量疾病的治疗。
Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix- producing osteoblasts(1) and bone resorption by osteoclasts(2). The demonstration that the anorexigenic hormone leptin(3-5) inhibits bone formation through a hypothalamic relay(6,7) suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U ( NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms(8,9). Here we show that Nmu-deficient ( Nmu(-/-)) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell- based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system - mediated inhibition of bone formation(6,7) was abolished in Nmu(-/-) mice, which show an altered bone expression of molecular clock genes ( mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild- type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin- dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action(10), our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.