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
基本信息
- 批准号:10586047
- 负责人:
- 金额:$ 33.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AchievementAffectAgeAgingAnatomyAreaBiologicalBiological ModelsBiologyBiophysicsBone ResorptionBone remodelingCellsCommunicationComplexConnexin 43ConnexinsCoupledCuesCyclic AMPDataDefectDinoprostoneEffectivenessEffector CellEnsureEventExposure toFailureFemurFundingGap JunctionsGoalsGrantGrowth FactorHomeostasisHormonesIn VitroInositol PhosphatesKnowledgeLocationMaintenanceMechanicsMethodsModelingMolecularMusMutationOsteoblastsOsteoclastsOsteocytesOsteogenesisOsteoporosisPTH genePathway interactionsPhenotypePhysiologicalPlayPopulationPublishingRegulationRoleSecond Messenger SystemsSignal TransductionSourceStimulusSurfaceTNFSF11 geneTestingThickTissuesTranslationsbonebone cellbone healthbone massbone qualityconditional knockoutcortical boneexperiencegap junction channelin vivoinsightintercellular communicationmechanical loadmechanical signalmechanotransductionmolecular massosteoprogenitor celloverexpressionreceptor expressionresponserestraintsegregationskeletalskeletal disorderskeletal tissuetransmission process
项目摘要
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,缝隙连接蛋白43在达到峰值的过程中起着关键的,尽管是复杂的作用。
骨量、骨质量的维持以及对间歇性甲状旁腺激素骨合成作用的反应
激素和机械负荷。连接蛋白43缺失对骨骼的影响因年龄、负重、废用和
甚至是解剖位置这种复杂性挑战了关于连接蛋白43在骨中功能的教条,
某些背景下。虽然生物物理数据表明不同分子量的第二信使可以通过
通过连接蛋白43通道,我们对哪些信使与生物学相关,
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解开看似矛盾的发现至关重要,
connexin 43在骨中的功能,了解骨稳态。由新的和已发布的数据支持,并使用
cAMP作为模型第二信使,我们的目标是测试信号的想法,这些信号出现在一个有反应的骨的子集中,
细胞,然后通过连接蛋白43跨越距离分布到适当的效应细胞,以协调组织
重塑在缺乏连接蛋白43的情况下,这种对刺激的不对称反应和无法分享它导致了
信号在细胞亚群中的非预期分配,破坏生理功能。这些事件,反过来,
导致应答细胞中的过度信号传导和邻近群体中信号传导的缺失。这
使协调的骨重建分离并导致低骨质量。这种信号划分模型可以解释
这些看似矛盾的发现,在皮质骨的基础上,并在响应负荷连接蛋白43缺乏。我们
将测试中心假设,cAMP通过连接蛋白43细胞间通讯作为一个分子,
标尺,在空间上定义骨重建。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限定了与发生协调的骨重建的源的距离。我们将
从两个方面来检验这个假设。第一个将研究连接蛋白43如何在空间上调节cAMP
成骨细胞和骨细胞活性以及皮质骨重塑。第二部分将研究分子结果
connexin 43-通信cAMP对皮质骨机械反应的幅度和/或敏感性的影响。我们
令人兴奋的初步数据表明,cAMP启动骨细胞对机械提示的反应,至少部分是通过
调节TRPV 4依赖性机械转导途径的敏感性。总的来说,这些研究将解决
关于骨细胞传输信号的根本重要问题,
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。
对骨机械反应性和合成代谢反应的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph P. Stains其他文献
Characterization of a pollen-expressed gene encoding a putative pectin esterase ofPetunia inflata
- DOI:
10.1007/bf00043881 - 发表时间:
1994-06-01 - 期刊:
- 影响因子:3.800
- 作者:
Jing-Hong Mu;Joseph P. Stains;Teh-hui Kao - 通讯作者:
Teh-hui Kao
Microtubule Remodeling Contributes to the Loss of Force and Power in Aging Skeletal Muscle
- DOI:
10.1016/j.bpj.2019.11.2740 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Humberto Cavalcante Joca;Anicca Harriot;Jenna Leser;Andrew Coleman;Guoli Shi;Joseph P. Stains;Christopher W. Ward - 通讯作者:
Christopher W. Ward
Microtubule Mechanotransduction through Nox2-ROS Initiates TRPV4 Calcium Influx and Purinergic Calcium Oscillations that Regulate Osteocyte Mechano-Sensing
- DOI:
10.1016/j.bpj.2018.11.2041 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Katrina M. Williams;Nicole Gould;Derek Jones;Ramzi Khairallah;Christopher W. Ward;Joseph P. Stains - 通讯作者:
Joseph P. Stains
Increased Microtubule Density and Level of Detyrosination Occur Coincident with Sarcomere Malformations in Diseased and Aging Skeletal Muscle
- DOI:
10.1016/j.bpj.2018.11.2188 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Anicca Harriot;Andrew Coleman;Shama R. Iyer;Camilo Venagas;Guoli Shi;Richard M. Lovering;Humberto C. Joca;Joseph P. Stains;Chris W. Ward - 通讯作者:
Chris W. Ward
Joseph P. Stains的其他文献
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{{ truncateString('Joseph P. Stains', 18)}}的其他基金
Mechanisms of osteocyte mechano-signaling and sclerostin regulation
骨细胞机械信号传导和硬化素调节机制
- 批准号:
10395929 - 财政年份:2018
- 资助金额:
$ 33.98万 - 项目类别:
Mechanisms of osteocyte mechano-signaling and sclerostin regulation
骨细胞机械信号传导和硬化素调节机制
- 批准号:
9922216 - 财政年份:2018
- 资助金额:
$ 33.98万 - 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
- 批准号:
9230816 - 财政年份:2013
- 资助金额:
$ 33.98万 - 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
- 批准号:
8415654 - 财政年份:2013
- 资助金额:
$ 33.98万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 33.98万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 33.98万 - 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
- 批准号:
8628047 - 财政年份:2013
- 资助金额:
$ 33.98万 - 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
- 批准号:
8828565 - 财政年份:2013
- 资助金额:
$ 33.98万 - 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
- 批准号:
9022410 - 财政年份:2013
- 资助金额:
$ 33.98万 - 项目类别:
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