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，白细胞介素-1 β（IL-1 β）和肿瘤坏死因子-α（TNF-α）不仅导致骨关节炎和类风湿性关节炎中软骨基质的破坏，而且还减少软骨特异性基质蛋白（包括II型胶原和聚集蛋白聚糖）的合成。我们在已发表的和初步的研究中表明，IL-1 β通过多种信号通路在转录水平上抑制软骨细胞中II型胶原基因（COL 2A 1）的表达。此外，我们发现一种新的ETS因子ESE-1，它是由ILi 1 β和TNF-α诱导的，与COL 2A 1启动子结合并直接抑制其活性，表明这种转录因子在调节COL 2A 1基因表达中起关键作用。我们的假设是，IL-1 β诱导的COL 2A 1基因表达抑制是由ESE-1作为主要的转录调节因子介导的，并涉及多种信号通路和转录因子，直接或间接地与ESE-1相互作用。对于这些研究，我们已经开发了永生化的人软骨细胞系，其保留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是参与IL-1 β介导的COL 2A 1基因抑制的主要转录因子;（2）涉及p38 MAPK、JNK、Jak 3、IKK/IkappaB和P13 K/Akt激酶级联的多种信号通路直接或间接地通过ESE-1抑制IL-1 β诱导的COL 2A 1基因表达;（3）ESE-1通过涉及其它IL-1 β诱导的转录因子和组成性因子的特异性蛋白-DNA和蛋白-蛋白相互作用对COL 2A 1表达发挥其阻遏物功能;（4）ESE-1对COL 2A 1表达的抑制导致软骨细胞依赖性的软骨基质合成抑制。这些研究将允许解剖参与IL-1 β对COL 2A 1基因转录调控的特异性信号通路和分子调控系统。这些结果也可能导致开发更特异和有效的治疗方法，用于阻断IL-1 β对OA和RA等疾病中软骨基质基因及其产物的不良影响。