Role of ESE1 Regulation of Type II Collagen in Cartilage

描述(申请人提供)：在关节组织中产生的分解代谢和促炎细胞因子，白介素1β(IL-1β)和肿瘤坏死因子-α(TNF-α)，不仅有助于破坏骨关节炎和类风湿性关节炎的软骨基质，而且还减少软骨特有的基质蛋白的合成，包括II型胶原和聚集素。我们在已发表的和初步的研究中发现，IL-1β通过多条信号通路在转录水平上抑制软骨细胞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，它是由ILi1β和TNF-α诱导的，它与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基因表达方面发挥了关键作用。我们的假设是，IL-1β诱导的COL2A1基因表达抑制是由ESE-1作为主要转录调节因子介导的，涉及直接或间接与ESE-1相互作用的多个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类软骨细胞系，它们保留了软骨细胞特有的表型和对细胞因子的反应。ESE-1是参与IL-1β抑制COL2A1基因表达的主要转录因子；(2)p38MAPK、JNK、JAK3、IKK/IkappaB和P13K/Akt激酶等多条信号通路通过ESE-1直接和间接地转导IL-1β抑制COL2A1基因表达的假设；(3)ESE-1通过涉及其他IL-1β诱导的转录因子和构成因子的特异性蛋白-DNA和蛋白-蛋白相互作用发挥抑制COL2A1基因表达的作用；(4)ESE-1抑制COL2A1的表达导致软骨细胞依赖抑制软骨基质的合成。这些研究将允许剖析参与IL-1β对COL2A1基因转录调控的特定信号通路和分子调控系统。这些结果还可能导致开发更具体和有效的治疗方法，以阻断IL-1β对软骨基质基因及其产物在诸如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.