Role of ESE1 Regulation of Type II Collagen in Cartilage

ESE1 对软骨中 II 型胶原蛋白的调节作用

• 批准号: 6801386
• 负责人: MARY B GOLDRING
• 金额: $ 34万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801386
• 关键词: JAK kinase; JUN kinase; biological signal transduction; cartilage development; cell line; chondrocytes; collagen; gel mobility shift assay; gene expression; gene induction /repression; immunoprecipitation; interleukin 1; microarray technology; mitogen activated protein kinase; phosphatidylinositol 3 kinase; protein protein interaction; tissue /cell culture; transcription factor; transfection; tumor necrosis factor alpha; yeast two hybrid system

DESCRIPTION (provided by applicant): The catabolic and proinflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced in the joint tissues, not only contribute to the destruction of cartilage matrix in osteoarthntis and rheumatoid arthritis, but also decrease the synthesis of cartilage-specific matrix proteins, including type II collagen and aggrecan. We have shown in published and preliminary studies that IL-1beta suppresses expression of the type II collagen gene (COL2A1) in chondrocytes at the transcriptional level via multiple signaling pathways. Furthermore, we have found that a novel ETS factor, ESE-1, which is induced by ILi1beta and TNF-alpha, binds to the COL2A1 promoter and directly suppresses its activity, indicating a pivotal role for this transcription factor in regulating COL2A1 gene expression. Our hypothesis is that IL-1beta-induced suppression of COL2A1 gene expression is mediated by ESE-1 as the primary transcriptional regulator and involves multiple signaling pathways and transcription factors that interact directly or indirectly with ESE-1. For these studies, we have developed immortalized human chondrocyte cell lines, which retain chondrocyte-specific phenotype and responses to cytokines. The Specific Aims will test the hypotheses that: (1) ESE-1 is the primary transcription factor involved in IL-1beta-mediated suppression of the COL2A 1 gene; (2) multiple signaling pathways involving p38 MAPK, JNK, Jak3, IKK/IkappaB and P13K/Akt kinase cascades transduce IL-1beta-induced suppression of COL2A1 gene expression, both directly and indirectly, via ESE-1; (3) ESE-1 serves its repressor function on COL2A1 expression via specific protein-DNA and protein-protein interactions involving other IL-1beta-induced transcription factors and constitutive factors; and (4) ESE-1 suppression of COL2A1 expression results in chondrocyte-dependent inhibition of cartilage matrix synthesis. These studies will permit dissection of the specific signaling pathways and molecular regulatory systems involved in transcriptional regulation of the COL2A1 gene by IL-1beta. These results may also lead to the development of more specific and effective therapeutic approaches for blocking the adverse effects of IL-1beta on cartilage matrix genes and their products in disorders such as OA and RA.

描述（由申请人提供）：关节组织中产生的分解代谢和促炎细胞因子，肠介菌1Beta（IL-1Beta）和肿瘤坏死因子 - α（TNF-Alpha）（TNF-Alpha）在关节组织中产生的不仅有助于在Osteoararthatition和Rhryailition Aryaigiotio contiosion Arigiotio Arigiotio contiosiotio contiotio connition Arigiotio contiotio contiotio contiotio contiotio contiotio contilition Ariogiotio artiosioid Ariogioid Ariogioid artrix中产生的分解。基质蛋白，包括II型胶原蛋白和Aggrecan。我们在已发表的初步研究中表明，IL-1BETA抑制了通过多个信号传导途径在转录水平的软骨细胞中II型胶原基因（COL2A1）的表达。此外，我们发现，由ILI1BETA和TNF-ALPHA诱导的新型ETS因子ESE-1与COL2A1启动子结合并直接抑制其活性，表明该转录因子在调节Col2a1基因表达中的转录因子具有关键作用。我们的假设是，IL-1Beta诱导的COL2A1基因表达抑制是由ESE-1介导的，作为主要的转录调节剂，涉及多种信号传导途径和与ESE-1直接或间接相互作用的转录因子。在这些研究中，我们开发了永生的人软骨细胞细胞系，该细胞系保留了软骨细胞特异性表型和对细胞因子的反应。具体目的将检验以下假设：（1）ESE-1是IL-1BETA介导的Col2a 1基因抑制IL-1BETA介导的主要转录因子； （2）涉及P38 MAPK，JNK，JAK3，IKK/IKAPPAB和P13K/AKT激酶的多个信号传导途径cascades cascades cascades cascades cascade trandduce iL-1Beta诱导的Col2a1基因表达的抑制直接和间接地通过ESE-1通过ESE-1； （3）ESE-1通过特异性蛋白-DNA和蛋白质 - 蛋白质相互作用在COL2A1表达上发挥其抑制作用功能，涉及其他IL-1Beta诱导的转录因子和本构成因子； （4）ESE-1对COL2A1表达的抑制会导致软骨细胞依赖性软骨基质合成的抑制作用。这些研究将允许通过IL-1Beta对Col2A1基因的转录调节的特定信号通路和分子调节系统进行解剖。这些结果还可能导致开发更具体和有效的治疗方法，以阻止IL-1Beta对软骨基质基因及其产物（例如OA和RA）的产物的不良影响。