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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.

骨质疏松症和肉质疏松症是骨骼和肌肉丢失的疾病，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，提示共同的致病机制。和/或肌肉和骨骼之间的串音。康奈特治疗骨质疏松靶向破骨细胞或成骨细胞活性维持骨量，但骨细胞已过度摄取。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，而成骨细胞和破骨细胞功能的调节骨细胞的Wnt/3-catenin途径可能在骨量调节中起中心作用。我们的实验室采取了一种独特的方法来研究成骨细胞-骨细胞之间的相互作用，使用荧光实时成像骨细胞和器官培养模型的研究进展。我们已经证明，骨表面的成骨细胞是在活的成骨细胞中，运动细胞和ECM蛋白的组装是一个高度动态的过程，即与细胞运动相结合。我们还表明，由骨细胞产生的硬化素和WNTS可以改变成骨细胞的运动和分化功能。在这些观察的基础上，这个项目将检查从动态角度看成骨细胞对成骨细胞功能的调控。总体假设是骨细胞通过控制运动通过Wnt/p-catenin信号通路调节骨量成骨细胞的特性和分化功能，这一调节过程是由肌肉- 骨骼串扰，在老化过程中受损，导致骨骼受损。为了解决这一假设，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关于成骨细胞和骨细胞谱系以及GFP标记的细胞外信号蛋白的报道。的影响骨细胞产生的Wnt和skerostin的调节将使用抑制剂、基因沉默和转基因方法。确定来自肌肉的串扰是否改变成骨细胞对骨细胞的控制在成肌细胞分化的Viti-o模型以及转基因和衰老受损或增强的模型中的功能将使用肌肉功能。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的丢失。相关性(请参阅即时消息)：骨质疏松症和骨质疏松症是骨骼和肌肉丢失的疾病，通常在老年人中一起发生。这是一个重大的公共卫生问题。这项研究的目标是确定有助于这些条件协调发展的分子和细胞机制。这研究可能导致开发治疗这些疾病的新方法。