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Pharmacological study on bone metabolism by nervous activity

神经活动对骨代谢的药理学研究

基本信息

批准号：
17591956
负责人：
TOGARI Akifumi
金额：
$ 2.36万
依托单位：
Aichi Gakuin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

The vertebrate skeleton is richly innervated with adrenergic and peptidergic nerve terminals, and these play important roles in bone remodelling. Recently showed that increased sympathetic nervous activity causes bone loss via an increase in bone resorption and a decrease in bone formation. Increased bone resorption is based on the stimulation of both osteoclast formation and osteoclast activity. And we also demonstrated that human osteoblastic as well as osteoclastic cells are equipped with adrenergic receptors (Ars) and neuropeptide receptors and that they constitutively express diffusible axon guidance molecules known to function as a chemoattractant and/or chemorepellent for growing nerve fibers. These findings suggest that the extension of axons of sympathetic and peripheral sensory neurons to osteoblastic and osteoclastic cells is required for the dynamic neural regulation of local bone metabolism. However, while several studies have shown a functional nerve-bone cell interplay, … More whether both osteoblastic and osteoclastic cells activation occurs as a direct response to neuronal activation or requires an intermediary cell is unclear. Therefore, we examined direct nerve-osteoblastic cell communication by using an in vitro co-culture model comprising mouse osteoblastic cells, MC3T3-El, and neurite-spouting mouse superior cervical ganglia. Following loading with the calcium fluorophore Fluo-3, neurite-osteoblastic cell units were examined by confocal laser scanning microscopy. The addition of scorpion venom (SV) elicited neurite activation (i.e., Ca^<2+> mobilization) and, after a lag period, osteoblastic Ca^<2+> mobilization. The SV had no direct effect on the MC3T3-El cells in the absence of neurites. The addition of an α1-AR antagonist, prazosin concentration-dependently prevented the osteoblastic activation that resulted as a consequence of the neural activation by SV. Thus, our recent findings demonstrate that MC3T3-E1 activation, as judge by Ca^<2+> mobilization, can be a direct consequence of contact with a specific activated nerve fiber. This evidence obtained in vitro demonstrates that nerve-osteoblastic cell cross-talk can occur in the absence of an intermediary transducing cell and that noradrenaline is an important mediator of this communication. Several recent in vivo and in vitro studies have demonstrated a sympathomimetic action on bone formation and resorption via osteoblastic and osteoclastic cells, respectively, expressing α-and β-Ars. Less

脊椎动物骨骼富含肾上腺素能和肽能神经末梢，这些神经末梢在骨重塑中发挥着重要作用。最近表明，交感神经活动的增加通过骨吸收的增加和骨形成的减少导致骨质流失。骨吸收的增加是基于破骨细胞形成和破骨细胞活性的刺激。我们还证明，人类成骨细胞和破骨细胞都配备有肾上腺素能受体（Ars）和神经肽受体，并且它们组成型表达可扩散的轴突引导分子，已知这些分子可作为神经纤维生长的化学引诱剂和/或化学排斥剂。这些发现表明，局部骨代谢的动态神经调节需要交感神经和外周感觉神经元的轴突延伸至成骨细胞和破骨细胞。然而，虽然一些研究表明功能性神经骨细胞之间存在相互作用，但成骨细胞和破骨细胞的激活是否是对神经元激活的直接反应，还是需要中间细胞，尚不清楚。因此，我们通过使用包含小鼠成骨细胞、MC3T3-E1和神经突喷出小鼠颈上神经节的体外共培养模型来检查直接神经-成骨细胞通讯。加载钙荧光团 Fluo-3 后，通过共焦激光扫描显微镜检查神经突成骨细胞单元。添加蝎毒(SV)引起神经突激活(即Ca 2+ 动员)，并且在滞后期后引起成骨细胞Ca 2+ 动员。在不存在神经突的情况下，SV对MC3T3-E1细胞没有直接影响。添加 α1-AR 拮抗剂哌唑嗪浓度依赖性地阻止了由于 SV 神经激活而导致的成骨细胞激活。因此，我们最近的研究结果表明，根据Ca 2+ 动员判断，MC3T3-E1 激活可能是与特定激活神经纤维接触的直接结果。体外获得的证据表明，神经-成骨细胞间的交流可以在没有中间转导细胞的情况下发生，并且去甲肾上腺素是这种交流的重要介质。最近的几项体内和体外研究表明，分别通过表达 α-Ars 和 β-Ars 的成骨细胞和破骨细胞对骨形成和骨吸收具有拟交感神经作用。较少的