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: 10586047
• 负责人: Joseph P. Stains
• 金额: $ 33.98万
• 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/10586047
• 关键词: Achievement; 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; 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; Mutation; 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; bone; bone cell; bone health; bone mass; bone quality; conditional knockout; cortical bone; experience; gap junction channel; in vivo; insight; intercellular communication; mechanical load; mechanical signal; mechanotransduction; molecular mass; osteoprogenitor cell; overexpression; receptor expression; response; restraint; segregation; skeletal; skeletal disorder; skeletal tissue; transmission process

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.

项目概要 大量研究表明，connexin43 间隙连接在达到峰值的过程中发挥着关键但复杂的作用。 骨量、骨质量的维持以及对间歇性甲状旁腺骨合成代谢效应的反应 connexin43 缺失对骨骼的影响因年龄、负荷、废弃和使用而异。 这种复杂性甚至挑战了有关骨中连接蛋白 43 功能的教条。 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 connexin43 通道，我们对哪些信使具有生物学相关性、它们的 生物学后果，以及这些信号在骨细胞和骨细胞之间传播的范围或方向性 这些问题对于解开看似矛盾的发现至关重要。 connexin43 在骨骼中的功能以及了解骨骼稳态得到新发表的数据和使用的支持。 cAMP 作为第二信使模型，我们的目标是测试信号的想法，这些信号出现在响应性骨骼的子集中 然后通过 connexin43 将细胞分布到适当的效应细胞以协调组织 在缺乏连接蛋白43的情况下，这种对刺激的不对称反应和无法分享它会导致 细胞子集中的信号意外分离，进而破坏了生理功能。 导致响应细胞中信号传导过度，而邻近细胞群中信号传导缺失。 这种信号分配模型可以解释协调的骨重塑并导致骨质量低下。 这些看似矛盾的发现表明皮质骨中连接蛋白 43 缺乏，并且对负荷有反应。 将检验中心假设，即 cAMP 通过 connexin43 的细胞间通讯充当分子 标尺，在空间上定义骨重塑，因此，连接蛋白 43 允许长距离翻译的能力。 细胞之间的生物信号定义了与协调骨重塑发生的源的距离。 通过两个目的来检验这一假设，第一个目的是检验 connexin43 如何在空间上调节 cAMP。 第二个将检查成骨细胞和骨细胞活性以及皮质骨重塑的分子后果。 connexin43 通讯的 cAMP 对皮质骨机械反应的幅度和/或敏感性的影响。 令人兴奋的初步数据表明，cAMP 至少部分地通过以下方式启动骨细胞对机械信号的反应： 总的来说，这些研究将解决 TRPV4 依赖性机械传导途径的敏感性。 关于骨细胞传输的信号、范围和后果的根本性重要问题 他们的沟通会影响骨重塑，并将有助于解释连接蛋白43的矛盾影响 对间歇性 PTH 的骨机械反应和合成代谢反应的影响。