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: 7784750
• 负责人: MARY B GOLDRING
• 金额: $ 35.88万
• 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/7784750
• 关键词: Accounting; Affect; Age; 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; Matrix Metalloproteinases; Modeling; Molecular; Mus; NOS2A gene; Nuclear; Operative Surgical Procedures; 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; arm; articular cartilage; base; cell type; chromatin immunoprecipitation; collagenase; collagenase 3; cytokine; early onset; 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）：最初描述为上皮特异性ETS（ESE）-1（小鼠中的Elf 3），我们发现这种新的转录因子通过与COL 2A 1启动子结合并与Sox 9和CBP相互作用抑制II型胶原基因（COL 2A 1）表达，并且ESE-1免疫染色在骨关节炎（OA）患者软骨的浅表和中间区域增加。我们的初步数据表明，ESE-1通过结合MMP-13启动子中的ETS/PEA 3位点并与Runx 2和AP-1协同作用来增加MMP-13的转录。与野生型小鼠相比，Ese 1/Elf 3缺陷小鼠中MMP-13蛋白的缺乏和OA的cho/+小鼠模型的关节软骨中Ese 1表达的增加进一步表明其在OA期间失调的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）什么样的信号通路诱导并激活ESE-1调节MMP-13和其他靶点？我们将使用原代小鼠和人类软骨细胞和细胞系来表征参与ESE-1在MMP 13和其他基因靶点调节中的诱导和作用的信号传导和转录机制，包括在基础和炎症条件下确定ESE-1作用的结构/功能关系。(2)Ese 1/Elf 3缺陷是否可以保护或减轻OA手术和遗传小鼠模型中的软骨损失，如果是，其作用机制是什么？我们将采用Ese 1/Elf 3基因敲除小鼠进行非遗传性实验诱导（手术）OA和Cho/+小鼠模型的年龄依赖性OA和地图的基因表达在发病和发展过程中的OA的敏感，原位基因表达分析和其他技术的目的1。(3)ESE-1过表达是否会影响小鼠膝关节因衰老或手术OA而发生或进展？我们将产生Tet-Off诱导的Ese 1转基因小鼠，以检查过量的ESE-1本身是否启动或加速手术诱导的OA，并揭示ESE-1依赖性机制是否与OA进展的程度相关。通过将体外研究的见解应用于小鼠模型中的离体和原位方法的早期和晚期事件分析，我们将获得对引发和进展的分子事件的理解，这将导致开发用于创伤或衰老所致OA的新型靶向治疗。 公共卫生相关性：我们最近的研究结果指出，一种新的转录因子，ESE-1，在骨关节炎（OA）的软骨重塑的调节中发挥着关键作用，并促使我们研究ESE-1被激活和调节软骨降解酶，基质金属蛋白酶-13的表达的机制。因此，我们将利用ESE-1基因敲除和条件转基因小鼠，以确定其在非遗传实验诱导（手术）OA和遗传为基础的自发性OA在衰老过程中的作用，通过应用体外研究的见解，分析早期和晚期事件的离体和原位方法。这些研究将提供对引发和进展的潜在分子事件的理解，并导致创伤和衰老所致OA的新型靶向治疗的开发。