ESE 1 a novel transcriptional regulator of cartilage remodeling

ESE 1 一种新型软骨重塑转录调节因子

• 批准号: 8223260
• 负责人: MARY B GOLDRING
• 金额: $ 34.48万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223260
• 关键词: Accounting; Affect; Aging; Attenuated; Binding; Biological Assay; Cartilage; Cartilage Matrix; Cell Line; Chondrocytes; Collagen; Collagen Gene; Complex; DNA Binding; Data; Degenerative polyarthritis; Dependency; Development; Disease; Enzymes; Epithelial; Event; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic; Genetic Transcription; Genomics; Histones; Human; In Situ; In Vitro; Inflammatory; Inflammatory Response; Knee joint; Knock-out; Knockout Mice; Knowledge; Lead; Maps; Modeling; Molecular; Mus; NOS2A gene; Nuclear; Operative Surgical Procedures; PEA3; PTGS2 gene; Patients; Peptide Hydrolases; Post-Translational Protein Processing; Proteins; Proteoglycan; Proteomics; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Site; Staging; Stimulus; Structure-Activity Relationship; Techniques; Tetanus Helper Peptide; Therapeutic Intervention; Time; Tissues; Transcription Factor AP-1; Transgenic Mice; Transgenic Organisms; Trauma; Up-Regulation; Wild Type Mouse; age related; aggrecanase; arm; articular cartilage; base; cell type; chromatin immunoprecipitation; collagenase; collagenase 3; cytokine; early onset; human ELF3 protein; in vivo Model; insight; mouse model; non-genetic; novel; overexpression; promoter; public health relevance; sensor; time interval; transcription factor

DESCRIPTION (provided by applicant): Described originally as Epithelial Specific ETS (ESE)-1 (Elf3 in mouse), we have found that this novel transcription factor suppresses type II collagen gene (COL2A1) expression by binding to the COL2A1 promoter and interacting with Sox9 and CBP and that ESE-1 immunostaining is increased in superficial and midzone regions of cartilage from patients with osteoarthritis (OA). Our preliminary data show that ESE-1 increases the transcription of matrix metalloproteinase (MMP)-13 by binding to ETS/PEA3 sites in the MMP13 promoter and cooperating with Runx2 and AP-1. The absence of MMP-13 protein in the Ese1/Elf3-deficient mouse and the increased Ese1 expression in the articular cartilage of the cho/+ mouse model of OA compared to wild type mice further suggest its pivotal role in de-regulated cartilage remodeling during OA. Thus, we hypothesize that ESE-1 is a critical transcriptional regulator of cartilage remodeling during OA progression. The Specific Aims are: (1) What are the signaling pathways that induce and activate ESE-1 to regulate MMP-13 and other targets? We will use primary mouse and human chondrocytes and cell lines to characterize the signaling and transcriptional mechanisms involved in the induction and action of ESE-1 in the regulation of MMP13 and other gene targets, including the structure/function relationships that determine ESE-1 actions under basal and inflammatory conditions. (2) Does Ese1/Elf3-deficiency protect against or attenuate cartilage loss in surgical and genetic mouse models of OA, and if so, what are its mechanisms of action? We will employ Ese1/Elf3 knockout mice subjected to non-genetic experimentally induced (surgical) OA and the Cho/+ mouse model of age-dependent OA and map gene expression during onset and progression of OA by sensitive, in situ gene expression analysis and other techniques developed in Aim 1. (3) Does ESE-1 over-expression affect the onset or progression of OA in mouse knee joints due to aging or surgical OA? We will generate Tet-Off-inducible Ese1 transgenic mice to examine whether excess ESE-1, by itself, initiates or accelerates surgically induced OA and reveal if ESE-1-dependent mechanisms correlate with the extent of OA progression. By applying insights from in vitro studies to the analysis of early and late events by ex vivo and in situ approaches in the mouse models, we will gain understanding of molecular events underlying initiation and progression that will lead to the development of novel targeted therapies for OA due to trauma or aging. PUBLIC HEALTH RELEVANCE: Our recent findings point to a critical role for a novel transcription factor, ESE-1, in the regulation of cartilage remodeling in osteoarthritis (OA) and have prompted us to examine the mechanisms by which ESE-1 is activated and regulates expression of the cartilage-degrading enzyme, matrix metalloproteinase-13. Thus, we will make use of ESE-1 knockout and conditional transgenic mice to determine its role in non-genetic experimentally-induced (surgical) OA and in genetically based spontaneous OA during aging by applying insights from in vitro studies to the analysis of early and late events by ex vivo and in situ approaches. These studies will provide understanding of molecular events underlying the initiation and progression and lead to the development of novel targeted therapies for OA due to trauma and aging.

描述（由申请人提供）：最初被描述为上皮特异性ETS (ESE)-1（小鼠Elf3），我们发现这种新型转录因子通过结合COL2A1启动子并与Sox9和CBP相互作用来抑制II型胶原基因（COL2A1）的表达，并且在骨关节炎（OA）患者的软骨表面和中间区域增加了ESE-1免疫染色。我们的初步数据表明，ESE-1通过结合MMP13启动子中的ETS/PEA3位点，并与Runx2和AP-1协同作用，增加了基质金属蛋白酶(MMP)-13的转录。与野生型小鼠相比，Ese1/ elf3缺失小鼠中MMP-13蛋白的缺失和cho/+小鼠OA模型中关节软骨中Ese1表达的增加进一步表明其在OA过程中去调控软骨重塑中的关键作用。因此，我们假设ESE-1是OA进展过程中软骨重塑的关键转录调节因子。具体目的是：(1)诱导和激活ESE-1调控MMP-13等靶点的信号通路是什么？我们将使用小鼠和人的原代软骨细胞和细胞系来表征在MMP13和其他基因靶点的调控中诱导和作用ESE-1的信号传导和转录机制，包括在基础和炎症条件下决定ESE-1作用的结构/功能关系。(2)在骨性关节炎的手术和遗传小鼠模型中，缺乏Ese1/ elf3是否能预防或减轻软骨损失？如果是，其作用机制是什么？我们将使用Ese1/Elf3敲除小鼠进行非遗传实验诱导（手术）OA和Cho/+小鼠年龄依赖性OA模型，并通过敏感、原位基因表达分析和Aim 1中开发的其他技术绘制OA发病和进展过程中的基因表达图谱。(3) ESE-1过表达是否影响小鼠膝关节因衰老或手术性OA的发病或进展？我们将产生et- off诱导的Ese1转基因小鼠，以检验过量的ESE-1本身是否启动或加速手术诱导的OA，并揭示ESE-1依赖机制是否与OA进展程度相关。通过将体外研究的见解应用于小鼠模型中离体和原位方法的早期和晚期事件分析，我们将了解发生和进展的分子事件，这将导致创伤或衰老引起的OA的新型靶向治疗的发展。