Biophysical Regulation of Chondrocyte Differentiation

软骨细胞分化的生物物理调节

基本信息

批准号：
7365209
负责人：
QIAN CHEN
金额：
$ 26.34万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-30 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7365209
关键词：
Affect Biomechanics Blocking Antibodies Bone Morphogenetic Proteins Cartilage Cartilage Matrix Cell Nucleus Cells Cellular Mechanotransduction Chondrocytes Collagen Collagen Gene Condition Cues DEC1 gene DEC1 protein DNA Microarray Chip DNA Microarray format Data Degenerative polyarthritis Depth Differentiation and Growth Elements Environment Erinaceidae Extracellular Matrix Filament Fracture Healing Frequencies Funding Gene Activation Gene Expression Genes Genetic Transcription Genome Goals Growth Hour Hypertrophy In Vitro Indium Joints Knowledge Luciferases Maps Mechanical Stimulation Mechanics Mediating Messenger RNA Microarray Analysis Mitogen-Activated Protein Kinases Molecular Mutation Natural regeneration Osteoarthrosis Deformans Pathogenesis Pathway interactions Play Polymerase Chain Reaction Process Production Regulation Reporter Genes Research Personnel Role Signal Pathway Signal Transduction Skeletal Development Testing Time Transgenic Mice base cartilage matrix protein extracellular in vivo Model kinase inhibitor matrilin 3 morphogens osteogenin programs promoter response transcription factor

Affect Biomechanics Blocking Antibodies Bone Morphogenetic Proteins Cartilage Cartilage Matrix Cell Nucleus Cells Cellular Mechanotransduction Chondrocytes Collagen Collagen Gene Condition Cues DEC1 gene DEC1 protein DNA Microarray Chip DNA Microarray format Data Degenerative polyarthritis Depth Differentiation and Growth Elements Environment Erinaceidae Extracellular Matrix Filament Fracture Healing Frequencies Funding Gene Activation Gene Expression Genes Genetic Transcription Genome Goals Growth Hour Hypertrophy In Vitro Indium Joints Knowledge Luciferases Maps Mechanical Stimulation Mechanics Mediating Messenger RNA Microarray Analysis Mitogen-Activated Protein Kinases Molecular Mutation Natural regeneration Osteoarthrosis Deformans Pathogenesis Pathway interactions Play Polymerase Chain Reaction Process Production Regulation Reporter Genes Research Personnel Role Signal Pathway Signal Transduction Skeletal Development Testing Time Transgenic Mice base cartilage matrix protein extracellular in vivo Model kinase inhibitor matrilin 3 morphogens osteogenin programs promoter response transcription factor

展开

项目摘要

Biophysical signals play important roles in regulating cartilage growth and regeneration. During skeletal development and fracture healing, mechanical load-induced matrix deformation induces the process of chondrocyte proliferation and differentiation. This process is also activated in osteoarthritic cartilage where altered cell-matrix interaction results in an abnormal mechanical microenvironment. Therefore, the pathways by which a mechanical signal is transduced from extracellular matrix to the nucleus to stimulate chondrocyte proliferation and differentiation need to be better understood. The long-term goal of this study is to analyze the molecular mechanisms underlying matrix deformation-regulated cartilage growth. Data generated from current funding period suggest a hypothesis in which mechanical signals regulate cartilage growth by a two- step process. First, transduction of mechanical signals from matrix to the cell involves both matrilin-1 and -3, which form an extracellular regulatory circuit of a mechanostat, with matrilin-1 forming pericellular filaments transducing mechanical signals and matrilin-3 antagonistic to filament formation. Second, in response to mechanical signals, chondrocytes induce the production of BMP and activate its downstream transcriptional factors, which in turn regulate gene expression and chondrocyte differentiation. This hypothesis will be tested systematically and in depth using both in vitro and in vivo models in the next funding period. We will analyze how mechanical signal transduction to the cell is regulated by pericellular matrilin filaments (SA 1), identify the transcriptional factors required for mechanical stimulation of chondrocyte differentiation (SA 2), and determine the role of BMP signaling in mechanical activation of a gene promoter in cartilage (SA 3). These knowledge will be important for understanding the fundamental signaling mechanisms underlying mechanical activation of chondrocyte proliferation, differentiation, and gene expression, which occur during skeletal development, fracture healing, and osteoarthritis pathogenesis.

生物物理信号在调节软骨生长和再生方面起着重要作用。在骨骼期间开发和断裂愈合，机械负载诱导的基质变形引起的过程软骨细胞增殖和分化。此过程也在骨关节炎软骨中激活细胞矩阵相互作用改变会导致异常的机械微环境。因此，路径通过将机械信号从细胞外基质转导到细胞核以刺激软骨细胞扩散和分化需要更好地理解。这项研究的长期目标是分析基质变形调节的软骨生长的分子机制。生成的数据当前的资金期间表明了一个假设，即机械信号通过两个 - 步骤过程。首先，机械信号从基质到细胞的转导涉及矩阵1和-3，哪个形成机械仪的细胞外调节电路转导机械信号和母素-3对细丝形成的拮抗作用。第二，回应机械信号，软骨细胞诱导BMP的产生并激活其下游转录因素又调节基因表达和软骨细胞分化。该假设将在下一个体外和体内模型进行系统和深入测试资金期。我们将分析机械信号转导向细胞的如何受细胞周围的调节基质蛋白丝（SA 1），确定机械刺激所需的转录因子软骨细胞分化（SA 2），并确定BMP信号传导在A机械激活中的作用软骨中的基因启动子（SA 3）。这些知识对于理解基本知识很重要软骨细胞增殖，分化和机械激活的信号传导机制基因表达，发生在骨骼发育，断裂愈合和骨关节炎发病机理中发生。