Role of Transcription Factor ERG in Skeletogenesis

转录因子 ERG 在骨骼发生中的作用

基本信息

批准号：
7390647
负责人：
Maurizio Pacifici
金额：
$ 32.45万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-15 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390647
关键词：
A Mouse Ablation Adult Affect Aging Agreement Biological Bone Marrow Cells Cartilage Cell Line Cell Surface Receptors Cell Therapy Cells Chondrocytes Cloning Complex Condition Data Defect Degenerative polyarthritis Development Down-Regulation ERG gene Elements Embryo Epiphysial cartilage Exhibits Family Family member Funding Future Gene Expression Genes Growth Human Hypertrophy Individual Joints Knockout Mice Knowledge Lead Life Limb structure Maintenance Molecular Mus Neonatal Organ Culture Techniques Osteoarthrosis Deformans Osteogenesis Other Finding Partner in relationship Pathology Patients Pattern Phenotype Phosphorylation Population Property RNA Splicing Regulation Reporter Research Personnel Role Signal Pathway Signaling Molecule Skeletal system Smad Proteins Smad protein Staging Stem cells Stream Structure Testing Therapeutic Transgenic Mice Transgenic Organisms Variant articular cartilage base bone functional restoration gain of function growth differentiation factor 5 insight long bone member mouse model postnatal prevent programs promoter recombinase response transcription factor

项目摘要

During limb skeletogenesis chondrocytes follow two developmental paths and produce permanent articular cartilage persisting through life or transient growth plate cartilage in which the cells mature, hypertrophy, and are replaced by bone. Though the critical importance of this developmental bifurcation for skeletal formation and function is widely recognized, the underlying mechanisms of regulation remain unclear, particularly at the molecular level. In the previous funding period, we focused on the transcription factor ERG and its variant C-1-1. Gain-of-function studies with chick and human C-1-1 show that: (a) C-1-1 is able to impose a stable and articular-like phenotype over the entire limb chondrocyte population, blocking growth plate formation, chondrocyte maturation and bone formation; (b) C-1-1 counteracts action of the pro-maturation transcription factor Runx2; and (c) the joint master regulator GDF-5 rapidly induces ERG/C-1-1 expression in developing synovial joints. These and other findings lead to our central hypotheses for this competitive continuation proposal: (a) C-1-1 acting down-stream of GDF-5 contributes to formation of permanent articular chondrocytes; and (b) C-1-1 in turn inhibits Runx2 function, maintains the permanent status of the cells, and prevents maturation and hypertrophy. Our aims are: (i) to functionally characterize murine ERG variants by cell and explant cultures and transgenic approaches;(ii) determine the consequences of conditional ERG gene ablation during development or postnatal life, using GDF-5-Cre and GDF-5-CreER mice; and (iii) determine the mechanisms by which GDF-5 triggers ERG expression by signaling pathways and promoter action, and how ERG/C-1-1 inhibits Runx2 function. The project will produce fundamental insights into genesis and function of articular chondrocytes. It should also generate mouse models of degenerative joint disease that could be used to test future gene- and cell-based therapies for joints conditions common to osteoarthritic patients and aging individuals.

在肢体骨骼生成期间，软骨细胞遵循两条发育路径并产生永久关节软骨在生命或短暂生长板软骨中持续存在，其中细胞成熟，肥大，并被骨头所取代。虽然这种发育分叉在骨骼上的重要性形成和功能被广泛认可，调节的潜在机制尚不清楚，特别是在分子水平上。在上一个资金期间，我们专注于转录因子 ERG及其变体C-1-1。对小鸡和人类C-1-1的功能性研究表明：（a）C-1-1是能够在整个肢体软骨细胞种群中施加稳定的关节样表型生长板形成，软骨细胞的成熟和骨形成；（b）C-1-1抵消了 pro成熟转录因子runx2; （c）联合主管GDF-5迅速诱导 ERG/C-1-1在发育的滑膜中表达。这些和其他发现导致我们的中心该竞争性延续提案的假设：（a）C-1-1的GDF-5行动下游贡献形成永久性关节软骨细胞；（b）C-1-1依次抑制RUNX2功能，维持细胞的永久状态，并防止成熟和肥大。我们的目标是：（i）功能在功能上以细胞和外植体培养和转基因方法来表征鼠ERG变体；（ii）确定在发育或产后生活期间有条件ERG基因消融的后果 GDF-5-CRE和GDF-5-CREER小鼠；（iii）确定GDF-5触发ERG的机制通过信号通路和启动子的作用以及ERG/C-1-1抑制RUNX2功能的表达。这项目将对关节软骨细胞的起源和功能产生基本见解。它也应该生成退化性关节疾病的小鼠模型，可用于测试未来的基因和骨关节炎患者和老年人常见的关节条件的基于细胞的疗法。