Role of a TGF-? Regulated Gene in Human and Mouse Osteoblasts and Skeleton

TGF-的作用？

• 批准号: 8669729
• 负责人: John R. Hawse
• 金额: $ 39.36万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669729
• 关键词: Address; Affect; American; Animals; Attention; Biology; Bone Density; Bone Development; Bone Diseases; Bone Regeneration; Cell physiology; Clinical Research; DNA Binding; Data; Defect; Development; Disease; Estrogen Replacement Therapy; Estrogens; Female; Fracture; Funding; Gender; Gene Expression; Genes; Genetic Polymorphism; Health Care Costs; Homeostasis; Human; In Vitro; Knockout Mice; Knowledge; Laboratories; Link; Lithium Chloride; Maintenance; Maps; Mediating; Molecular; Molecular Profiling; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteoporosis; Outcome; Ovariectomy; Pathway interactions; Phenotype; Play; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Skeletal Development; Skeleton; Testing; Tissue-Specific Gene Expression; Transgenic Mice; Transgenic Organisms; United States; Variant; Woman; base; bone; bone mass; drug development; in vivo Model; interest; men; novel; novel strategies; repaired; response; skeletal; skeletal abnormality; skeletal disorder; skeletal injury; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Osteoporosis is a bone disease affecting nearly 1 in 3 women worldwide and over 55% of all Americans resulting in health care costs exceeding 19 billion dollars annually in the United States alone. Since the discovery of the TGF? inducible early gene-1 (TIEG) by our laboratory, we have demonstrated that loss of TIEG expression in mice results in multiple defects in osteoblasts and osteoclasts and confers a gender specific osteopenic phenotype affecting only female animals. Recently, TIEG has been identified as one of only a few genes whose altered expression levels or allelelic variations associate with decreased bone mass and osteoporosis in humans. During the past funding period, we have shown that TIEG expression is essential for estrogen signaling in bone and have identified a novel role for TIEG in mediating canonical Wnt signaling in the skeleton. These observations are of significant interest since estrogen remains one of the most important regulators of bone homeostasis in both men and women and since Wnt signaling is essential for normal bone development and maintenance. For these reasons, it is crucial to understand the regulation of these pathways in the skeleton. In this proposal, we present evidence that TIEG enhances the Wnt signaling pathway via dual mechanisms whereby it directly suppresses the expression of sclerostin and serves as a transcriptional co- activator for ?-catenin. Furthermore, our data suggest that TIEG serves as a direct link between the estrogen and canonical Wnt pathways in bone. Based on these observations, our central hypothesis is that TIEG is a crucial component of canonical Wnt signaling and serves a central role in regulating cross-talk between the estrogen and Wnt pathways in the skeleton. In order to test this hypothesis, the following Specific Aims are proposed: 1): Characterize the regulation of sclerostin gene expression by TIEG and determine its contribution to the observed osteopenic phenotype of TIEG knockout mice; 2): Characterize the ability of TIEG to enhance canonical Wnt signaling through co-activation of ?-catenin; and 3) Determine if the gender specific (female only) osteopenic phenotype of TIEG KO mice results from defective cross-talk between the estrogen and canonical Wnt signaling pathways in bone. To address these Specific Aims, we will employ in vitro approaches to identify the molecular mechanisms by which TIEG suppresses sclerostin expression in osteocytes and enhances ?-catenin function in osteoblasts. Additionally, we will utilize multiple in vivo models and approaches to dissect the role of TIEG in regulating canonical Wnt pathway activity and cross-talk between estrogen and Wnt signaling in the skeleton. Considering the fundamental roles of estrogen and Wnt signaling in bone, as well as the present day targeting of these pathways for the treatment of osteoporosis, it is essential to understand the role of TIEG in regulating these two pathways. Completion of the proposed studies is therefore expected to provide significant knowledge with regard to developing novel strategies to treat this debilitating disease.

描述（由申请人提供）：骨质疏松症是一种骨病，影响全球近三分之一的女性和超过 55% 的美国人，仅在美国每年的医疗费用就超过 190 亿美元。自从发现TGF以来？通过我们实验室的诱导早期基因 1 (TIEG)，我们证明小鼠体内 TIEG 表达缺失会导致成骨细胞和破骨细胞的多种缺陷，并赋予仅影响雌性动物的性别特异性骨质减少表型。最近，TIEG 被确定为少数表达水平改变或等位基因变异与人类骨量减少和骨质疏松症相关的基因之一。在过去的资助期间，我们已经证明 TIEG 表达对于骨骼中的雌激素信号传导至关重要，并确定了 TIEG 在介导骨骼中经典 Wnt 信号传导中的新作用。这些观察结果非常有意义，因为雌激素仍然是男性和女性骨稳态最重要的调节剂之一，而且 Wnt 信号对于正常的骨骼发育和维持至关重要。由于这些原因，了解骨骼中这些途径的调节至关重要。在本提案中，我们提出证据表明 TIEG 通过双重机制增强 Wnt 信号通路，从而直接抑制硬化蛋白的表达并充当 β-连环蛋白的转录共激活剂。此外，我们的数据表明 TIEG 是骨骼中雌激素和经典 Wnt 通路之间的直接联系。基于这些观察，我们的中心假设是 TIEG 是经典 Wnt 信号传导的重要组成部分，并在调节骨骼中雌激素和 Wnt 通路之间的串扰中发挥核心作用。为了检验这一假设，提出以下具体目标： 1)：表征 TIEG 对硬化素基因表达的调节，并确定其对观察到的 TIEG 敲除小鼠骨质减少表型的贡献； 2)：表征 TIEG 通过共激活 β-catenin 增强经典 Wnt 信号传导的能力； 3) 确定 TIEG KO 小鼠的性别特异性（仅限雌性）骨质减少表型是否是由于雌激素和骨中典型 Wnt 信号通路之间的串扰缺陷造成的。为了实现这些具体目标，我们将采用体外方法来确定 TIEG 抑制骨细胞中硬化蛋白表达并增强成骨细胞中 β-连环蛋白功能的分子机制。此外，我们将利用多种体内模型和方法来剖析 TIEG 在调节典型 Wnt 通路活性以及骨骼中雌激素和 Wnt 信号传导之间的串扰中的作用。考虑到雌激素和 Wnt 信号在骨骼中的基本作用，以及目前这些途径治疗骨质疏松症的目标，了解 TIEG 在调节这两条途径中的作用至关重要。因此，完成拟议的研究预计将为开发治疗这种使人衰弱的疾病的新策略提供重要的知识。