Spatial Control of Bone Remodeling by Gap Junction-Communicated cAMP

项目总结 大量研究表明连接蛋白43缝隙连接在顶峰的实现过程中发挥着关键的作用，尽管复杂。 骨量、骨质量的维持以及对间歇性甲状旁腺的骨合成代谢效应的反应 荷尔蒙和机械负荷。连接蛋白43缺失对骨骼的影响因年龄、负荷、停用和 甚至是解剖学上的位置。这种复杂性挑战了关于连接蛋白43在骨骼中的功能的教条。 某些特定的背景。虽然生物物理数据表明，不同分子质量的第二信使可以通过 通过连接蛋白43通道，我们几乎不了解哪些信使在生物学上是相关的，他们的 生物学后果，以及这些信号在骨细胞之间传播的范围或方向性 成骨细胞。这些问题对于揭开这些看似自相矛盾的发现至关重要 缝隙连接蛋白43‘S在骨骼中发挥作用，并了解骨的动态平衡。由新的和已发布的数据支持，并使用 坎普作为第二信使的模型，我们的目标是测试在响应骨骼的子集中产生的信号的想法 细胞，然后由连接蛋白43跨距离分布到适当的效应细胞，以协调组织 改建。在没有连接蛋白43的情况下，这种对刺激的不对称反应和不能分享它导致 细胞子集中信号的无意分割，扰乱生理功能。这些事件，反过来， 导致在反应细胞中过度信号，而在邻近群体中没有信号。这 解偶联协调骨重塑，导致骨质量低下。这种信号划分模型可以解释 这些看似自相矛盾的发现是皮质骨中连接蛋白43缺乏的基础和对负荷的反应。我们 将检验cAMP通过连接蛋白43进行细胞间通讯的中心假说 尺子，在空间上定义了骨骼重塑。因此，连接蛋白43允许远距离翻译的能力 细胞之间的生物信号定义了发生协调骨重建的来源的距离。我们会 从两个目的来检验这一假设。第一项研究将研究连接蛋白43如何在空间上调节cAMP。 成骨细胞和骨细胞活性与皮质骨重塑。第二部分将研究分子后果。 连接蛋白43传递的cAMP对皮质骨力学反应的幅度和/或敏感性的影响。我们的 令人兴奋的初步数据显示，cAMP启动了骨细胞对机械提示的反应，至少部分是通过 调节依赖于TRPV4的机械转导通路的敏感性。总而言之，这些研究将解决 关于骨骼细胞传递的信号的根本重要问题，范围和后果 它们的通讯影响骨重建，并将有助于解释连接蛋白43的矛盾影响 间歇性甲状旁腺激素的骨力学反应和合成代谢反应。

PROJECT SUMMARY Numerous studies show that connexin43 gap junctions play a critical, albeit complex, role in the achievement of peak bone mass, maintenance of bone quality, and the response to the bone anabolic effects of intermittent parathyroid hormone and mechanical load. The skeletal effects of connexin43 deletions differ based on age, loading, disuse, and even anatomical location. This complexity has challenged the dogma regarding the function of connexin43 in bone in certain contexts. While biophysical data have shown that second messengers of varying molecular mass can pass through connexin43 channels, we have little insight into the which messengers are biologically relevant, their biological consequences, and the range or directionality with which these signals propagate between osteocytes and osteoblasts. These issues are fundamentally important to unravelling the seemingly paradoxical findings for connexin43’s functions in bone and to understand bone homeostasis. Supported by new and published data and using cAMP as a model second messenger, our goal is to test the idea that signals, which arise in a subset of responsive bone cells, are then distributed by connexin43 across distances to the appropriate effector cells to coordinate tissue remodeling. In the absence of connexin43, this asymmetrical response to the stimuli and inability to share it results in unintended partitioning of signals in a subset of cells, disrupting the physiological function. These events, in turn, result in hyper-signaling in the responding cells and the absence of signaling in neighboring populations. This uncouples coordinated bone remodeling and leads to low bone quality. This model of signal partitioning could explain these seemingly paradoxical findings for connexin43 deficiency in cortical bone basally and in response to load. We will test the central hypothesis that intercellular communication of cAMP through connexin43 acts as a molecular ruler, spatially defining bone remodeling. Thus, the ability of connexin43 to permit long-distance translation of biological signals between cells defines the distance from a source that coordinated bone remodeling occurs. We will examine this hypothesis in two aims. The first will examine how connexin43 communicated cAMP spatially regulates osteoblast and osteocyte activity and cortical bone remodeling. The second will examine the molecular consequence of connexin43-communicated cAMP on the magnitude and/or sensitivity of the cortical bone mechano-response. Our exciting preliminary data show that cAMP primes the response of osteocytes to mechanical cues, at least in part, by modulating the sensitivity of a TRPV4-dependent mechano-transduction pathway. In total, these studies will address fundamentally important questions about the signals being transmitted by bone cells, the range and consequence with which their communication impacts bone remodeling and will help to explain the paradoxical impacts of connexin43 on bone mechano-responsiveness and anabolic responses to intermittent PTH.