The Role of LRP5 in Bone Response to Mechanical Loading

LRP5 在骨机械负荷反应中的作用

基本信息

批准号：
8121537
负责人：
MARK Louis JOHNSON
金额：
$ 29.84万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8121537
关键词：
Accounting Address Adult Age Binding Biochemical Bone Diseases Bone Surface Cell Line Cell Nucleus Cell physiology Complex Data Dependence Development Dinoprostone Event Feedback Forearm Gene Expression Gene Targeting Genes Healthcare Systems Human In Vitro Indomethacin Integrins Knock-out LDL-Receptor Related Protein 1 Laboratories Lead Ligands Literature Maintenance Measures Mechanics Mediating Modeling Molecular Mus Mutation Nuclear Translocation Osteoblasts Osteocytes Osteogenesis Osteoporosis Pathway interactions Pattern Pharmaceutical Preparations Phosphorylation Play Population Positioning Attribute Prevention strategy Principal Investigator Prostaglandin E Receptor Prostaglandin Production Prostaglandins Publishing Receptor Activation Refractory Regulation Reporter Research Role Signal Pathway Signal Transduction Skeleton Staging Testing Time Transgenic Mice Transgenic Organisms Woman Work autocrine base bone bone cell bone loss bone mass cell type dentin matrix protein 1 fluid flow gain of function human disease in vitro Model in vivo kindred lipoprotein receptor related protein 5 men novel novel strategies paracrine prevent prostaglandin EP2 receptor protein phosphatase inhibitor-2 receptor receptor binding research study response skeletal disorder tool

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis afflicts 25 million women and men in the US per year and burdens the health care system with over 20 billion dollars per year. As the US population ages and lives longer, development of prevention strategies and new treatments for bone loss become even more crucial. The Principal Investigator identified a gene, Lrp5, responsible for high bone mass in a human kindred and evidence now exists that this molecule is involved in bone mass regulation through its role in the mechanotransduction pathway. In this proposal, we have developed a unifying hypothesis and model that integrates PGE2 and the Wnt/(-catenin signaling pathways and accounts for the role of Lrp5 in regulating bone cell function in response to loading. We will test the hypothesis that crosstalk between the prostaglandin and Wnt/( catenin signaling pathways in osteocytes is a key early event in the bone response to mechanical loading that sets into play an amplification mechanism to propagate the signal to load, resulting in a bone formation response. We propose that loading is first perceived by osteocytes followed by signal propagation to lining cells and osteoblasts on the bone surface. It is known that an early osteocyte response to mechanical loading is PGE2 release which functions in an autocrine/paracrine fashion to induce new bone formation. We propose this early event results in cross-talk with and activation of the Wnt/(-catenin pathway in a first step that is independent of Lrp5 receptor activation. This initial activation alters the expression of key factors that initiate the activation of Lrp5 through a paracrine/autocrine feedback mechanism, generating a secondary activation (amplification) of the Wnt/(-catenin pathway at the level of Lrp5. To test this hypothesis the following Specific Aims are proposed: 1) Determine when and which cell types (osteocytes, lining cells and osteoblasts) activate the Wnt/(-catenin signaling pathway in the adult skeleton in response to changes in mechanical load. 2) Determine the temporal relationship and crosstalk between the PGE2 and the Wnt/(-catenin signaling pathways in the bone cell response to mechanical loading. 3) Determine the mechanism by which the expression of known modulators of Lrp5 (Wnts, Dkks, Wise, Sost) are altered by mechanical loading in adult bone cells. These specific aims will be accomplished using complementary in vitro, in vivo and transgenic approaches to dissect the molecular mechanism for PGE2 initiated activation of (-catenin signaling and the role of Lrp5 in the response of bone to mechanical loading. These studies will provide a unifying model for integrating two pathways known to be important for bone responsiveness to mechanical loading, prostaglandin and Wnt/(-catenin signaling, and will result in a conceptual framework to integrate other important signaling pathways in bone (ATP, Ca2+ fluxes, integrin, etc.) into a paradigm that ultimately explains how bone responds to mechanical loading at the cellular and molecular level. This will lead to new approaches to treating and/or preventing osteoporosis.

描述（由申请人提供）：骨质疏松症每年困扰着美国 2500 万女性和男性，每年给医疗保健系统带来超过 200 亿美元的负担。随着美国人口老龄化和寿命延长，制定骨质流失的预防策略和新疗法变得更加重要。首席研究员发现了一种基因 Lrp5，它与人类亲属的高骨量有关，现在有证据表明该分子通过其在力传导途径中的作用参与骨量调节。在本提案中，我们开发了一个统一的假设和模型，整合了 PGE2 和 Wnt/(-catenin 信号通路)，并解释了 Lrp5 在响应负载调节骨细胞功能中的作用。我们将测试以下假设：骨细胞中的前列腺素和 Wnt/( 连环蛋白信号通路是骨对机械负荷反应的关键早期事件，它启动放大机制将信号传播到负荷，从而导致骨形成反应。我们建议负荷是首先由骨细胞感知，然后信号传播到骨表面的衬里细胞和成骨细胞众所周知，骨细胞对机械负荷的早期反应是 PGE2 释放，其以自分泌/旁分泌方式发挥作用，以诱导新骨形成。事件导致在第一步中与 Wnt/(-catenin 通路) 发生串扰并激活 Wnt/(-catenin 通路)，该通路与 Lrp5 受体激活无关。这种初始激活改变了通过以下方式启动 Lrp5 激活的关键因子的表达：旁分泌/自分泌反馈机制，在 Lrp5 水平产生 Wnt/(-catenin 通路) 的二次激活（放大）。为了检验这一假设，提出了以下具体目标：1) 确定何时以及哪些细胞类型（骨细胞、衬里细胞和成骨细胞）激活成人骨骼中的 Wnt/(-连环蛋白信号通路，以响应机械负荷的变化。2)确定骨细胞对机械负荷响应中 PGE2 和 Wnt/(-catenin 信号通路) 之间的时间关系和串扰。3) 确定已知 Lrp5 调节剂表达的机制（Wnts、Dkks、Wise、Sost）会因成体骨细胞中的机械负荷而改变。这些具体目标将通过使用互补的体外、体内和转基因方法来实现，以剖析 PGE2 启动的 (-catenin 信号传导激活) 的分子机制以及 Lrp5 在骨对机械负荷的响应中的作用。这些研究将提供一个统一的方法。该模型用于整合已知对骨骼对机械负荷的反应非常重要的两条途径：前列腺素和 Wnt/(-连环蛋白信号传导)，并将产生一个概念框架，以整合骨中其他重要的信号传导途径（ATP、Ca2+ 通量、整合素等）成为最终解释骨骼如何在细胞和分子水平上响应机械负荷的范例，这将导致治疗和/或预防骨质疏松症的新方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HBM Mice Have Altered Bone Matrix Composition and Improved Material Toughness.

HBM 小鼠改变了骨基质组成并提高了材料的韧性。

DOI：
发表时间：
2016
期刊：
影响因子：
4.2
作者：
Ross, Ryan D;Mashiatulla, Maleeha;Acerbo, Alvin S;Almer, Jonathan D;Miller, Lisa M;Johnson, Mark L;Sumner, D Rick
通讯作者：
Sumner, D Rick

Activation of β-catenin signaling in MLO-Y4 osteocytic cells versus 2T3 osteoblastic cells by fluid flow shear stress and PGE2: Implications for the study of mechanosensation in bone.

通过流体剪切应力和 PGE2 激活 MLO-Y4 骨细胞与 2T3 成骨细胞中的 β-连环蛋白信号：对骨机械感觉研究的影响。