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: 10358565
• 负责人: Joseph P. Stains
• 金额: $ 33.69万
• 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/10358565
• 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; mechanical signal; 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.

项目总结