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首页> 外文学位 >Role of transcription factor E4bp4 in glucocorticoid-mediated gene regulation in osteoblasts.
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Role of transcription factor E4bp4 in glucocorticoid-mediated gene regulation in osteoblasts.

机译：转录因子E4bp4在糖皮质激素介导的成骨细胞基因调控中的作用。

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摘要

Glucocorticoids (GCs) play important roles in the regulation of bone metabolism and the control of inflammatory disease. However, chronic GC treatment inhibits bone formation, induces osteoblast apoptosis, and is a leading cause of osteoporosis. Elucidation of the molecular pathways mediating GC action in osteoblasts is necessary for the development of novel patient therapies to treat inflammatory disease with fewer side effects. Previous studies have shown that GCs induce transcription factor E4bp4 in GC-induced lymphoid cell apoptosis. E4bp4 is a transcriptional repressor and primary response gene in osteoblasts. Studies have also shown that E4bp4 attenuates promoter activity of Cox-2, a GC-repressed gene, in osteoblasts. Thus, we aimed to study E4bp4 function in osteoblasts, shed light on the molecular details of its significance in bone, and perhaps reveal a novel regulatory pathway of GC effects on osteoblasts. Shown here is evidence that GCs induce E4bp4 expression. In turn, E4bp4 plays a role in mediating GC-regulated basal and inflammatory gene expression in osteoblasts and regulating osteoblast differentiation, function, and apoptosis. GCs induced sustained E4bp4 expression by Northern blot and real-time RT-PCR analysis in vitro, ex vivo, and in vivo. E4bp4 is a GC-induced primary response gene, and its induction was dose-dependent. GC-induced specific nuclear protein binding to the E4bp4 response element (EBPRE) contained E4bp4 by EMSAs and supershift assays. GCs attenuated expression of a promoter containing EBPRE sites in osteoblasts. E4bp4 overexpression inhibited osteogenic differentiation in primary osteoblasts and stable MC3T3-E1 cells in alkaline phosphatase assays and decreased expression of extracellular matrix proteins by real-time RT-PCR analysis. E4bp4-overexpressing primary osteoblasts failed to mineralize by Von Kossa staining. E4bp4 increased osteoblast apoptosis and cell death. E4bp4 knockdown by siRNA transfection attenuated GC-induced osteoblast apoptosis and cell death. Furthermore, microarray analysis demonstrated E4bp4 regulation of basal extracellular matrix gene expression in osteoblasts. E4bp4 downregulated inflammatory-induced osteoblastic Cox-2, IL-6, and iNOS expression, and E4bp4 directly bound to EBPRE-like sites in these promoters. We conclude that E4bp4 plays a critical role in osteoblast function and mediates GC effects on osteoblasts.
机译：糖皮质激素（GCs）在骨代谢的调节和炎性疾病的控制中起重要作用。然而，慢性GC治疗抑制骨形成，诱导成骨细胞凋亡，并且是骨质疏松症的主要原因。阐明介导成骨细胞中GC作用的分子途径对于开发新的治疗炎症反应副作用少的患者疗法是必要的。先前的研究表明，GC在GC诱导的淋巴样细胞凋亡中诱导转录因子E4bp4。 E4bp4是成骨细胞中的转录阻遏物和主要反应基因。研究还表明，E4bp4减弱成骨细胞中被GC抑制的基因Cox-2的启动子活性。因此，我们旨在研究E4bp4在成骨细胞中的功能，阐明其在骨中的重要性的分子细节，并可能揭示GC对成骨细胞影响的新型调节途径。这里显示的证据是GC诱导E4bp4表达。反过来，E4bp4在介导成骨细胞中GC调节的基础和炎症基因表达以及调节成骨细胞的分化，功能和凋亡中发挥作用。在体外，离体和体内，GC通过Northern印迹和实时RT-PCR分析诱导E4bp4持续表达。 E4bp4是GC诱导的主要反应基因，其诱导是剂量依赖性的。 GC诱导的特异性核蛋白与E4bp4反应元件（EBPRE）的结合通过EMSA和超位移测定包含E4bp4。 GC减弱了成骨细胞中含有EBPRE位点的启动子的表达。 E4bp4的过表达在碱性磷酸酶测定中抑制了原代成骨细胞和稳定的MC3T3-E1细胞的成骨分化，并通过实时RT-PCR分析降低了细胞外基质蛋白的表达。冯·科萨（Von Kossa）染色未表达E4bp4的原代成骨细胞。 E4bp4增加成骨细胞凋亡和细胞死亡。 siRNA转染的E4bp4敲低减弱了GC诱导的成骨细胞凋亡和细胞死亡。此外，微阵列分析表明成骨细胞中E4bp4调节基础细胞外基质基因表达。 E4bp4下调了炎症诱导的成骨细胞Cox-2，IL-6和iNOS的表达，并且E4bp4直接与这些启动子中的EBPRE样位点结合。我们得出结论，E4bp4在成骨细胞功能中起关键作用，并介导GC对成骨细胞的作用。

著录项

  • 作者

    Woo, Stacey Mayhene.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Biology Molecular.;Health Sciences Dentistry.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 128 p.
  • 总页数 128
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;预防医学、卫生学;口腔科学;
  • 关键词

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