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: 8644768
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644768
• 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 Profiling; 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.

描述（申请人提供）：最初被描述为上皮特异性 ETS (ESE)-1（小鼠中的 Elf3），我们发现这种新型转录因子通过与 COL2A1 启动子结合并与 Sox9 和 CBP 相互作用来抑制 II 型胶原基因 (COL2A1) 的表达，并且骨关节炎患者软骨浅表和中区区域的 ESE-1 免疫染色增加 （办公自动化）。我们的初步数据表明，ESE-1 通过与 MMP13 启动子中的 ETS/PEA3 位点结合并与 Runx2 和 AP-1 配合来增加基质金属蛋白酶 (MMP)-13 的转录。与野生型小鼠相比，Ese1/Elf3 缺陷小鼠中 MMP-13 蛋白的缺失以及 cho/+ OA 小鼠模型关节软骨中 Ese1 表达的增加进一步表明其在 OA 期间软骨重塑失调中的关键作用。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。具体目标是： (1) 诱导和激活 ESE-1 调节 MMP-13 和其他靶标的信号通路是什么？我们将使用原代小鼠和人类软骨细胞和细胞系来表征 ESE-1 在 MMP13 和其他基因靶标调节中的诱导和作用所涉及的信号传导和转录机制，包括决定 ESE-1 在基础和炎症条件下作用的结构/功能关系。 (2) Ese1/Elf3 缺陷是否可以防止或减轻 OA 手术和遗传小鼠模型中的软骨损失，如果可以，其作用机制是什么？我们将使用接受非遗传实验诱导（手术）OA的Ese1/Elf3敲除小鼠和年龄依赖性OA的Cho/+小鼠模型，并通过敏感的原位基因表达分析和目标1中开发的其他技术绘制OA发病和进展期间的基因表达图谱。（3）ESE-1过度表达是否会因衰老或手术而影响小鼠膝关节OA的发病或进展 办公自动化？我们将生成 Tet-Off 诱导的 Ese1 转基因小鼠，以检查过量的 ESE-1 本身是否会引发或加速手术诱导的 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对早期和晚期事件的分析，我们将了解引发和进展的分子事件，从而开发出针对创伤或衰老引起的骨关节炎的新型靶向疗法。

项目成果

Cells of the synovium in rheumatoid arthritis. Chondrocytes.

• DOI: 10.1186/ar2292
• 发表时间: 2007
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Otero M;Goldring MB
• 通讯作者: Goldring MB

Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism.

• DOI: 10.1136/ard.2008.098764
• 发表时间: 2008-12
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4
• 作者: Goldring MB;Otero M;Tsuchimochi K;Ijiri K;Li Y
• 通讯作者: Li Y

The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis.

• DOI: 10.1016/j.bbrc.2011.01.007
• 发表时间: 2011-02-18
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Imagawa K;de Andrés MC;Hashimoto K;Pitt D;Itoi E;Goldring MB;Roach HI;Oreffo RO
• 通讯作者: Oreffo RO

Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis.

• DOI: 10.1007/s11926-013-0375-6
• 发表时间: 2013-11
• 期刊: CURRENT RHEUMATOLOGY REPORTS
• 影响因子: 5
• 作者: Houard, Xavier;Goldring, Mary B.;Berenbaum, Francis
• 通讯作者: Berenbaum, Francis

Lectin binding studies on C-28/I2 and T/C-28a2 chondrocytes provide a basis for new tissue engineering and drug delivery perspectives in cartilage research.

• DOI: 10.1016/j.jconrel.2006.10.004
• 发表时间: 2007-01
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: S. Toegel;N. Harrer;V. E. Plattner;Frank M. Unger;H. Viernstein;M. Goldring;Franz Gabor;M. Wirth