Role of ESE1 Regulation of Type II Collagen in Cartilage

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)，不仅有助于骨关节炎和类风湿关节炎软骨基质的破坏，而且还会减少软骨特异性基质蛋白的合成，包括II型胶原和聚集蛋白。我们已发表的初步研究表明，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（COL2A1）的表达。此外，我们还发现了一种新的ETS因子，ESE-1，由ili1 β和tnf - α诱导，结合COL2A1启动子并直接抑制其活性，表明该转录因子在调节COL2A1基因表达中起关键作用。我们的假设是il -1 β诱导的COL2A1基因表达的抑制是由ESE-1作为主要的转录调节因子介导的，涉及多种直接或间接与ESE-1相互作用的信号通路和转录因子。在这些研究中，我们开发了永生化的人软骨细胞系，它保留了软骨细胞特异性表型和对细胞因子的反应。具体目标将测试以下假设：(1)ESE-1是参与il -1 β介导的COL2A 1基因抑制的主要转录因子；(2)涉及p38 MAPK、JNK、Jak3、IKK/IkappaB和P13K/Akt激酶级联的多种信号通路通过ESE-1直接或间接地介导il -1诱导的COL2A1基因表达抑制；(3) ESE-1通过与其他il -1 - β诱导的转录因子和构成因子的特异性蛋白- dna和蛋白相互作用，对COL2A1的表达起抑制作用；(4) ESE-1抑制COL2A1表达导致软骨细胞依赖性软骨基质合成的抑制。这些研究将允许解剖特定的信号通路和分子调控系统参与COL2A1基因的转录调节il -1 β。这些结果也可能导致开发更具体和有效的治疗方法，以阻断il -1 β对软骨基质基因及其产物在OA和RA等疾病中的不利影响。

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.