Spatial Control of Bone Remodeling by Gap Junction-Communicated cAMP

间隙连接通讯 cAMP 对骨重塑的空间控制

• 批准号: 9893064
• 负责人: Joseph P. Stains
• 金额: $ 34.55万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9893064
• 关键词: Achievement; Address; Affect; Age; Aging; Anatomy; Area; Biological; Biological Models; Biology; Biophysics; Bone Resorption; Bone remodeling; Cells; Communication; Complex; Connexin 43; Connexins; Coupled; Cues; Cyclic AMP; Data; Defect; Deletion Mutation; Dinoprostone; Effectiveness; Effector Cell; Ensure; Event; Exposure to; Failure; Femur; Funding; Gap Junctions; Goals; Grant; Growth Factor; Homeostasis; Hormones; In Vitro; Inositol Phosphates; Knowledge; Location; Maintenance; Mechanics; Methods; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; PTH gene; Pathway interactions; Phenotype; Physiological; Play; Population; Publishing; Regulation; Role; Second Messenger Systems; Signal Transduction; Source; Stimulus; Surface; TNFSF11 gene; Testing; Thick; Tissues; Translations; base; bone; bone cell; bone health; bone mass; bone quality; conditional knockout; cortical bone; density; experience; gap junction channel; in vivo; insight; intercellular communication; mechanical load; mechanotransduction; molecular mass; osteoprogenitor cell; overexpression; receptor expression; response; skeletal; skeletal disorder; skeletal tissue

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.

项目摘要 大量研究表明，连接连接连接在达到峰的实现中起着至关重要的，尽管是至关重 骨骼质量，骨质的维持以及对间歇性甲状旁腺骨合成代谢作用的反应 激素和机械负荷。 Connexin43的骨骼效应根据年龄，负载，废除和 甚至解剖位置。这种复杂性挑战了关于骨在骨骼中connexin43功能的教条 某些上下文。虽然生物物理数据表明，不同分子质量的第二使者可以通过 通过connexin43频道，我们几乎没有深入了解哪些使者在生物学上相关的，它们 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。这些问题对于揭示看似自相矛盾的发现至关重要 Connexin43在骨骼中起作用并了解骨稳态。由新的和已发布的数据支持，并使用 作为型号的第二使者的训练营，我们的目标是测试信号的想法，该想法是在响应式骨骼中产生的信号 然后，细胞通过connexin43分布在与适当效应细胞的距离之间，以协调组织 重塑。在没有connexin43的情况下，这种对刺激的不对称反应和无法共享的反应导致 单元子集中信号的意外分区，破坏了物理功能。这些事件反过来 导致响应细胞过度信号和相邻人群中没有信号传导。这 未连接的骨骼重塑，导致骨质质量低。这种信号分区模型可以解释 这些看似矛盾的发现，用于基本和负载的皮质骨缺乏。我们 将检验中心假设，即通过连接cannexin43的cAMP交流充当分子 统治者，在空间上定义骨骼重塑。这，connexin43的能力允许长途翻译 细胞之间的生物信号定义了与配位骨重塑的源的距离。我们将 在两个目标中检查这一假设。第一个将检查Connexin43如何在空间进行调节的Connexin43 成骨细胞和骨细胞活性和皮质骨重塑。第二个将检查分子后果 在皮质骨骼机械响应的大小和/或灵敏度上，连接的cook connexin43 comp。我们的 令人兴奋的初步数据表明，营地素骨细胞对机械提示的反应至少部分是 调节TRPV4依赖性机械转导途径的灵敏度。总的来说，这些研究将解决 关于骨细胞传输的信号的根本重要问题，与 它们的交流会影响骨骼重塑，并有助于解释Connexin43的矛盾影响 关于骨骼机械反应和对间歇性PTH的合成代谢反应。