A Neuronal Basis for the Osteocalcin Regulation of Bone Mass

项目摘要 多年来，神经元控制骨量的存在得到了许多不同的确认 善良。尽管这些绝不是神经元控制骨量的唯一例子，但交感神经 神经系统通过阻碍骨形成来抑制骨量的积累，而副交感神经 系统有利于骨量的增加。然而，调节骨量增加的神经元从来都不是 探索一种可能的方法来探索由于缺乏各种成骨细胞而引起的骨量表型。 衍生蛋白质。同样，神经元控制骨量的重要性往往没有得到重视。 在头面部研究过。这是令人惊讶的，因为颅骨和面部的骨骼中有许多成骨细胞 起源于神经脊细胞。骨钙素是骨骼中含量最丰富的非胶原蛋白。 细胞外基质缺乏，导致高骨量表型知之甚少。骨钙素 也是一种荷尔蒙，在它与本文所述新型受体结合后，它所支持的功能 儿茶酚胺在大脑中的合成及交感神经的活动 系统集中管理。与该功能无关，如本申请另一组初步结果所示， 骨钙素通过其所描述的第一个受体Cyprc6a发出信号来抑制副交感神经的活动 神经系统。骨钙素对自主神经系统的两种调节都会阻碍骨骼。 大量应计项目。因此，这些初步数据提供了两种可能的机制来解释从来没有发生过的事情 到目前为止的解释是：在缺乏骨钙素的小鼠中看到的高骨量表型。我们打算解决这个问题 通过研究骨钙素对颅面部及其他部位骨量的调节提出的问题 这具骨架的。本申请的具体目标是： 通过以下方法确定前脑GPR158的失活是否会导致高骨量 降低了同情的语气。 确定节后副交感神经元中Gprc6a的失活是否会导致 一种高骨量表型。 将通过抢救和遗传上位性实验测试骨钙素对 交感神经和/或副交感神经的声调解释了它对骨量增加的调节。

Project Summary The existence of a neuronal control of bone mass has received over the years many confirmations of various kind. Although those are by no means the only example of neuronal control of bone mass, the sympathetic nervous system inhibits bone mass accrual by hampering bone formation whereas the parasympathetic nervous system favors bone mass accrual. However, neuronal of regulation of bone mass accrual has never been explored as a possible means to explore bone mass phenotype caused by the absence of various osteoblast- derived proteins. Likewise, more often than not the importance of neuronal control of bone mass has not been studied in the craniofacial region. This is surprising since many osteoblasts in bones of the skull and face originate from neural crest cells. Osteocalcin is the most abundant non-collagenous protein of the bone extracellular matrix, the absence of which results in a poorly understood high bone mass phenotype. Osteocalcin is also an hormone and in that capacity it favors, following its binding to as novel receptor described in this application, the synthesis of catecholamine in the brain and thereby the activity of the sympathetic nervous system centrally. Independently of this function, as shown in another set of preliminary result of this application, osteocalcin signals through its first receptor described, Cyprc6a, to inhibit the activity of the parasympathetic nervous system. Both types of regulation of the autonomic nervous system by osteocalcin could hamper bone mass accrual. Hence, these preliminary data provide two possible mechanisms to explain what has never been explained until now: the high bone mass phenotype seen in mice lacking osteocalcin. We intend to address this question by studying the regulation of bone mass by osteocalcin in the craniofacial region, as well as in the rest of the skeleton. The Specific Aims of this application are:  To determine whether an inactivation of Gpr158 in the forebrain will result in a high bone mass by decreasing the sympathetic tone.  To determine whether an inactivation of Gprc6a in post-ganglionic parasympathetic neurons will result in a high bone mass phenotype.  To test through rescue and genetic epistasis experiments whether osteocalcin regulation of the sympathetic and/or parasympathetic tone explains its regulation of bone mass accrual.