Role of ATF-4 in the Anabolic Actions of PTH on Bone

ATF-4 在 PTH 对骨的合成代谢作用中的作用

• 批准号: 8494396
• 负责人: Guozhi Xiao
• 金额: $ 8.72万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-17 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494396
• 关键词: Role; ATF; Anabolic; Actions; PTH

DESCRIPTION (provided by applicant): Osteoporosis is a major public health problem that affects more than 10 million people in the US and results in 1.5 million fractures annually. Intermittent administration of parathyroid hormone (PTH) is the most effective current treatment for osteoporosis. PTH improves bone mass and bone microarchitecture, increases bone strength, and reduces the risk for fractures. However, the molecular mechanism underlying the anabolic actions of PTH on bone formation remains poorly understood. Gene deletion studies showed that activating transcription factor 4 (ATF4) is a critical factor for bone formation. The findings from our preliminary studies strongly suggest that PTH controls osteoblast-specific gene expression and bone formation, at least in part, through ATF4. The long-term goal of this project is to understand how PTH signals regulate osteoblast activity in bone formation. Our hypotheses are: i) PTH activates ATF4 by promoting its phosphorylation and protein-protein interactions with Runx2, and ii) ATF4 mediates the anabolic actions of PTH on bone. To test these hypotheses, we will pursue the following Specific Aims: Aim 1. Determine the mechanism used by PTH to regulate ATF4 and Runx2 transcriptional activity. To accomplish this aim: i) we will identify the PTH responsive phosphorylation sites in ATF4 and assess the functional significance of PTH-induced phosphorylation in ATF4 in cultured cells; ii) We will define the regions/amino acid residues within ATF4 and Runx2 that mediate the ATF4-Runx2 interactions; and iii) we will determine whether PTH signals increase ATF4-Runx2 binding and if these interactions are necessary for PTH actions in osteoblasts in vitro. Aim 2. Establish whether the anabolic actions of PTH require ATF4. We will determine if ATF4 is required for the anabolic actions of PTH in vivo using the ATF4-deficient mice and transgenic mice overexpressing ATF4 in osteoblasts. Aim 3. Determine whether ATF4-Runx2 interactions are required for normal and PTH-induced bone formation in vivo. This project will explore a novel mechanism to explain the anabolic actions of PTH and define new potential therapeutic targets for improved treatment of osteoporosis and other metabolic bone diseases.

描述（由申请人提供）：骨质疏松症是一个主要的公共卫生问题，在美国影响超过1000万人，每年导致150万例骨折。甲状旁腺激素（PTH）的间歇管理是目前最有效的治疗骨质疏松症。PTH改善骨量和骨微结构，增加骨强度，降低骨折风险。然而，PTH对骨形成的合成代谢作用的分子机制仍然知之甚少。基因缺失研究表明，激活转录因子4（ATF 4）是骨形成的关键因子。我们的初步研究结果强烈表明，PTH控制成骨细胞特异性基因表达和骨形成，至少部分，通过ATF 4。该项目的长期目标是了解甲状旁腺激素信号如何调节骨形成中的成骨细胞活性。我们的假设是：i）PTH通过促进其磷酸化和与Runx 2的蛋白质-蛋白质相互作用来活化ATF 4，和ii）ATF 4介导PTH对骨的合成代谢作用。为了验证这些假设，我们将追求以下具体目标：目标1。确定PTH调节ATF 4和Runx 2转录活性的机制。为实现这一目标：i）我们将鉴定ATF 4中PTH应答性磷酸化位点，并评估培养细胞中ATF 4中PTH诱导的磷酸化的功能意义; ii）我们将确定ATF 4和Runx 2内介导ATF 4-Runx 2相互作用的区域/氨基酸残基;和iii）我们将确定PTH信号是否增加ATF 4-Runx 2结合以及这些相互作用是否是体外成骨细胞中PTH作用所必需的。目标2.确定PTH的合成代谢作用是否需要ATF 4。我们将使用ATF 4缺陷小鼠和成骨细胞中过表达ATF 4的转基因小鼠来确定ATF 4是否是PTH体内合成代谢作用所必需的。目标3。确定ATF 4-Runx 2相互作用是否是体内正常和PTH诱导的骨形成所必需的。该项目将探索一种新的机制来解释PTH的合成代谢作用，并确定新的潜在治疗靶点，以改善骨质疏松症和其他代谢性骨病的治疗。

项目成果

Activating transcription factor 4 is critical for proliferation and survival in primary bone marrow stromal cells and calvarial osteoblasts.

• DOI: 10.1002/jcb.21888
• 发表时间: 2008-10-15
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Zhang, Xiaoyan;Yu, Shibing;Galson, Deborah L.;Luo, Min;Fan, Jie;Zhang, Jian;Guan, Youfei;Xiao, Guozhi
• 通讯作者: Xiao, Guozhi

Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone.

• DOI: 10.1371/journal.pone.0007583
• 发表时间: 2009-10-23
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yu S;Franceschi RT;Luo M;Fan J;Jiang D;Cao H;Kwon TG;Lai Y;Zhang J;Patrene K;Hankenson K;Roodman GD;Xiao G
• 通讯作者: Xiao G