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

TGF-β 调控基因在人和小鼠成骨细胞和骨骼中的作用

• 批准号: 9081563
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9081563
• 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; Transcription Coactivator; Transforming Growth Factor beta; Transgenic Mice; Transgenic Organisms; United States; Variant; Woman; base; beta catenin; bone; bone mass; drug development; estrogenic; in vivo Model; interest; men; novel; novel strategies; novel therapeutics; 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 TGFß 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 ß-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 ß-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 ß-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，影响着全世界近三分之一的女性和超过 55% 的美国人，自早期发现 TGFß 诱导剂以来，仅在美国每年的医疗费用就超过 190 亿美元。基因1（TIEG）由我们的实验室证明，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。这些观察结果非常有趣，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 信号传导是骨骼中最重要的调节因子。由于这些原因，了解骨骼中这些通路的调节至关重要，我们提出了 TIEG 通过双重机制增强 Wnt 信号通路的证据，从而直接抑制 Wnt 的表达。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。是经典 Wnt 信号传导的重要组成部分，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，提出了以下具体目标： 1)：表征硬化素的调节。 TIEG 的基因表达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骨骼中雌激素和经典 Wnt 信号通路之间的缺陷串扰所致。 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。考虑到雌激素和 Wnt 信号在骨骼中的基本作用，以及目前针对这些通路的治疗，剖析 TIEG 在调节经典 Wnt 通路活性以及骨骼中雌激素和 Wnt 信号之间的串扰中的作用。骨质疏松症的研究，有必要了解 TIEG 在调节这两种途径中的作用，因此，完成拟议的研究有望为开发治疗这种衰弱疾病的新策略提供重要的知识。

项目成果

TGFbeta inducible early gene-1 (TIEG1) and cardiac hypertrophy: Discovery and characterization of a novel signaling pathway.

TGFbeta 诱导早期基因 1 (TIEG1) 和心脏肥大：新信号通路的发现和表征。

• 发表时间: 2007-02-01
• 影响因子: 4
• 作者: Rajamannan, Nalini M;Subramaniam, Malayannan;Abraham, Theodore P;Vasile, Vlad C;Ackerman, Michael J;Monroe, David G;Chew, Teng;Spelsberg, Thomas C
• 通讯作者: Spelsberg, Thomas C

TGFbeta inducible early gene-1 directly binds to, and represses, the OPG promoter in osteoblasts.

TGFbeta 诱导型早期基因 1 直接结合并抑制成骨细胞中的 OPG 启动子。

• 发表时间: 2010-01-29
• 影响因子: 3.1
• 作者: Subramaniam, M;Hawse, J R;Bruinsma, E S;Grygo, S B;Cicek, M;Oursler, M J;Spelsberg, T C
• 通讯作者: Spelsberg, T C

Krüppel-Like Factor 10 participates in cervical cancer immunoediting through transcriptional regulation of Pregnancy-Specific Beta-1 Glycoproteins.

Krüppel 样因子 10 通过妊娠特异性 Beta-1 糖蛋白的转录调节参与宫颈癌免疫编辑。

• 发表时间: 2018
• 影响因子: 4.6
• 作者: Marrero;Taniguchi;Subramaniam, Malayannan;Hawse, John R;Pitel, Kevin S;Arreola;Huerta;Ponce;Figueroa;Gomez;Martinez
• 通讯作者: Martinez

Histone demethylase JARID1B/KDM5B is a corepressor of TIEG1/KLF10.

组蛋白去甲基化酶 JARID1B/KDM5B 是 TIEG1/KLF10 的辅阻遏物。

• 发表时间: 2010-10-22
• 影响因子: 3.1
• 作者: Kim, Joanna;Shin, Sook;Subramaniam, Malayannan;Bruinsma, Elizabeth;Kim, Tae;Hawse, John R;Spelsberg, Thomas C;Janknecht, Ralf
• 通讯作者: Janknecht, Ralf

TIEG1 enhances Osterix expression and mediates its induction by TGFβ and BMP2 in osteoblasts.

TIEG1 增强 Osterix 表达并介导成骨细胞中 TGFβ 和 BMP2 的诱导。

• 发表时间: 2016-02-12
• 影响因子: 3.1
• 作者: Subramaniam, Malayannan;Pitel, Kevin S;Withers, Sarah G;Drissi, Hicham;Hawse, John R
• 通讯作者: Hawse, John R