Osteocyte Control of Osteoblast Dynamics with Aging

骨细胞对衰老过程中成骨细胞动力学的控制

基本信息

批准号：
8281074
负责人：
SARAH L DALLAS
金额：
$ 25.92万
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：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8281074
关键词：
Address Age Aging Anabolic Agents Bone Density Bone Diseases Bone Matrix Bone Resorption Bone Surface Cell Culture Techniques Cells Clinical Data Dendrites Development Disease Enhancers Extracellular Matrix Extracellular Matrix Proteins Fluorescent Probes Fracture Gene Silencing Genes Goals Growth Image Imaging Techniques Laboratories Lead Life Mechanics Mediator of activation protein Modeling Molecular Motion Muscle Muscle Contraction Muscle Development Muscle function Mutation Myoblasts Organ Organ Culture Techniques Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Pathway interactions Perception Play Population Process Property Proteins Public Health Regulation Reporter Research Research Personnel Risk Role Signal Pathway Signal Transduction Skeleton Speed System Therapeutic Transgenic Mice Transgenic Organisms aged bone bone cell bone mass cell assembly cell motility cellular imaging extracellular in vivo inhibitor/antagonist mineralization mouse model muscle form muscle strength neuronal cell body novel novel therapeutic intervention osteoblast differentiation overexpression prevent sarcopenia

项目摘要

Osteoporosis and Sarcopenia are diseases of bone and muscle loss that represent a major clinical problem in the aged population. These conditions often occur together, suggesting common pathogenic mechanisms and/or crosstalk between muscle and bone. Cunent treatmente for osteoporosis target osteoclast or osteoblast activity to maintain bone mass, but tiie osteocyte has been overiooked. Exciting recent research has shown that osteocytes are major regulators of osteoblast and osteoclast function and that regulation of the Wnt/3-catenin pathway by osteocytes may play a central role inregulationof bone mass. Our laboratory has taken a unique approach to examining osteoblast-osteocyte interactions using fiuorescence live imaging approaches in bone cell and organ culture models. We have shown that osteoblasts on the bone surface are motile cells and that assembly of ECM proteins In living osteoblasts is a highly dynamic process that is integrated with cell motility. We have also shown that Sclerostin and Wnts, both produced by osteocytes, can alter osteoblast motility and differentiated function. Building on these observations, this project will examine osteocyte control of osteoblast function from a dynamic perspective. The overall hypothesis is that osteocytes regulate bone mass through the Wnt/p-catenin signaling pathway by controlling the motile properties and differentiated function of osteoblasts and that this regulatory process is modulated by muscle- bone crosstalk and is impaired during aging, leading to a compromised skeleton. To address this hypothesis, live cell imaging techniques will be used in young and aged transgenic mouse models expressing fluorescent reporters for osteoblast and osteocyte lineages and GFP-tagged extracellular matiix proteins. The effect of modulation of osteocyte-produced Wnt and sclerostin will be investigated using inhibitors, gene silencing and transgenic approaches. To determine whether crosstalk from muscle alters osteocyte control of osteoblast function, in viti-o models of myoblast differentiation and transgenic and aged models of impaired or enhanced muscle function will be used. These studies may lead to the way to novel therapeutic approaches for preventing loss of bone and muscle mass in the elderiy. RELEVANCE (See Instnictions): Osteoporosis and sarcopenia are diseases of bone and muscle loss that often occur togetiier in the aged population and represent a major public health problem. The goal ofthis research is to determine the molecular and cellular mechanisms that contribute to the co-ordinated development of these conditions. This research may lead to development of new treatment approaches for these diseases.

骨质疏松症和肌肉减少症是骨和肌肉损失的疾病，是一个主要的临床问题在老年人口中。这些情况经常同时发生，表明存在共同的致病机制和/或肌肉和骨骼之间的串扰。当前骨质疏松症的治疗目标是破骨细胞或成骨细胞活性维持骨量，但骨细胞却被忽视。令人兴奋的最新研究研究表明，骨细胞是成骨细胞和破骨细胞功能的主要调节者，并且调节骨细胞的Wnt/3-连环蛋白通路可能在骨量调节中发挥核心作用。我们的实验室采用荧光实时成像检查成骨细胞-骨细胞相互作用的独特方法骨细胞和器官培养模型的方法。我们已经证明骨表面的成骨细胞运动细胞和活成骨细胞中 ECM 蛋白的组装是一个高度动态的过程与细胞运动性相结合。我们还表明，骨细胞产生的 Sclerostin 和 Wnts 可以改变成骨细胞运动和分化功能。在这些观察的基础上，该项目将审查骨细胞从动态角度控制成骨细胞功能。总体假设是骨细胞通过 Wnt/p-catenin 信号通路控制运动来调节骨量成骨细胞的特性和分化功能，并且这种调节过程受到肌肉调节骨串扰并在衰老过程中受损，导致骨骼受损。为了解决这个假设，活细胞成像技术将用于表达荧光的年轻和老年转基因小鼠模型成骨细胞和骨细胞谱系以及 GFP 标记的细胞外 matiix 蛋白的报告基因。的效果将使用抑制剂、基因沉默和转基因方法。确定来自肌肉的串扰是否改变骨细胞对成骨细胞的控制功能，在成肌细胞分化的 viti-o 模型以及受损或增强的转基因和衰老模型中将使用肌肉功能。这些研究可能会带来新的治疗方法防止老年人骨骼和肌肉质量的损失。相关性（参见说明）：骨质疏松症和肌肉减少症是老年人经常同时发生的骨和肌肉损失的疾病人口并构成重大公共卫生问题。本研究的目标是确定有助于这些病症协调发展的分子和细胞机制。这研究可能会导致开发这些疾病的新治疗方法。