Nmp4/CIZ regulation of bone phenotype

Nmp4/CIZ 对骨表型的调节

• 批准号: 7650177
• 负责人: JOSEPH P BIDWELL
• 金额: $ 23.64万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650177
• 关键词: Adaptor Signaling Protein; Address; Adherens Junction; Apoptosis; Architecture; BMP2 gene; Bone Resorption; Cell Adhesion; Cell Proliferation; Cell membrane; Cells; Complement; Cytoskeleton; DNA Binding; Data; Diffusion; Dinoprostone; Disease; Docking; Enzymes; Event; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Signal Regulated Kinases; Focal Adhesions; Fracture; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Hormone Responsive; Hormones; Integrins; Knock-out; Knockout Mice; Link; Matrix Metalloproteinases; Mechanics; Mediating; Molecular; Mus; Names; Nuclear Envelope; Nuclear Matrix; Nuclear Matrix-Associated Proteins; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Parathyroid Hormones; Pathway interactions; Phenotype; Positioning Attribute; Predisposition; Property; Proteins; Public Health; Regulation; Research Personnel; Role; Screening procedure; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Skeleton; Stimulation of Cell Proliferation; Tissues; Tokyo; Transgenic Mice; Universities; Work; Zinc Fingers; base; bone; bone cell; bone mass; bone morphogenetic protein 2; bone turnover; collagenase 3; hormone regulation; human BCAR1 protein; human PTH protein; loss of function; new therapeutic target; novel; nucleocytoplasmic transport; osteoclastogenesis; osteopontin; programs; promoter; protein function; response; scaffold; skeletal; solid state; transcription factor

DESCRIPTION (provided by applicant): Osteoporosis is a major public health threat characterized by low bone mass leading to an increased susceptibility to skeletal fractures. Parathyroid hormone (PTH) treatment is a promising new therapy that stimulates bone formation, however the mechanisms underlying this anabolic response are largely unknown. The molecular basis underlying PTH-induced changes in osteoblast phenotype involves the integration of soluble signaling pathways with a solid-state scaffold, itself capable of transmitting information to target genes. The interlinking proteins of the extracellular matrix, the focal adhesions, the cytoskeleton, and the nuclear matrix comprise this scaffold or tissue matrix. Nmp4/CIZ (nuclear matrix protein 4/cas-interacting zinc finger protein) may integrate PTH activated soluble and solid-state signaling pathways with transcription. This protein is a PTH-responsive component of the osteoblast tissue matrix and a nucleocytoplasmic shuttling transcription factor. As a transcription factor, Nmp4/CIZ governs the amplitude of transcription induction (synergy control). For example, Nmp4/CIZ suppresses the increase in activity of specific osteoblast genes responding to PTH, prostaglandin E2, and bone morphogenetic protein 2. The loss of this function may contribute to the skeletal phenotype of Nmp4/CIZ knockout mice, which includes an enhanced skeletal response to PTH and BMP2. Our preliminary studies indicate that Nmp4/CIZ synergy control involves hormone regulation of Nmp4/CIZ-DNA binding activity and an interaction with Runx2. As a signaling molecule, Nmp4/CIZ may regulate osteoblast proliferation via an interaction with p130cas, an integrin- associated docking protein involved in mitogenesis. Nmp4/CIZ is also expressed in the osteoclast and our preliminary data indicate a role in osteoclastogenesis. We hypothesize that the functions of Nmp4/CIZ as signaling molecule and transcription factor are integrated in mediating PTH-induced changes in skeletal architecture. Wild type and Nmp4/CIZ genetically modified mice will be used to study the role of Nmp4/CIZ in mediating PTH-induced changes in bone phenotype. Osteoblasts and osteoclasts derived from these mice will be used to determine the functional role of Nmp4/CIZ as a signaling molecule and transcription factor in mediating bone cell response to hormone. The relevance of this work to public health is that it will identify a potential new therapeutic target for the treatment of osteoporosis.

描述（由申请人提供）：骨质疏松症是一种主要的公共卫生威胁，其特征是骨骼质量低，导致对骨骼骨折的敏感性增加。甲状旁腺激素（PTH）治疗是一种有希望的新疗法，可刺激骨形成，但是这种合成代谢反应的机制在很大程度上是未知的。分子基础基础PTH诱导的成骨细胞表型的变化涉及将可溶性信号通路与固态支架的整合，本身能够将信息传输到靶基因。细胞外基质，局灶性粘连，细胞骨架和核基质的相互联系的蛋白质包括该支架或组织基质。 NMP4/CIZ（核基质蛋白4/casteracting锌指蛋白）可能会将PTH活化的可溶性和固态信号通路与转录相结合。该蛋白是成骨细胞组织基质的PTH响应性成分和核质式穿梭转录因子。作为转录因子，NMP4/CIZ控制着转录诱导的幅度（协同控制）。例如，NMP4/CIZ抑制了对PTH，Prostaglandin E2和骨形态发生蛋白2响应的特定成骨细胞基因的活性增加。该功能的丧失可能有助于NMP4/CIZ敲除小鼠的骨骼表型，其中包括增强对PTH和PTH和BMP2的骨架响应。我们的初步研究表明，NMP4/CIZ协同控制涉及NMP4/CIZ-DNA结合活性的激素调节以及与Runx2的相互作用。作为信号分子，NMP4/CIZ可以通过与P130CA的相互作用（一种与有丝分裂发生有关的结构蛋白结合蛋白）进行相互作用来调节成骨细胞增殖。 NMP4/CIZ在破骨细胞中也表达，我们的初步数据表明在破骨细胞生成中起作用。我们假设NMP4/CIZ作为信号分子和转录因子的功能集成在介导PTH诱导的骨骼结构变化中。野生型和NMP4/CIZ遗传修饰的小鼠将用于研究NMP4/CIZ在介导PTH诱导的骨表型变化中的作用。源自这些小鼠的成骨细胞和破骨细胞将用于确定NMP4/CIZ作为信号分子和转录因子在介导骨细胞对激素反应中的功能作用。这项工作与公共卫生的相关性在于，它将确定治疗骨质疏松症的潜在新治疗靶标。

项目成果

Is HMGB1 an osteocyte alarmin?

• DOI: 10.1002/jcb.21572
• 发表时间: 2008-04-15
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Bidwell, Joseph P.;Yang, Jieping;Robling, Alexander G.
• 通讯作者: Robling, Alexander G.

Nmp4/CIZ closes the parathyroid hormone anabolic window.

Nmp4/CIZ 关闭甲状旁腺激素合成代谢窗口。

• DOI: 10.1615/critreveukargeneexpr.v22.i3.40
• 发表时间: 2012
• 期刊: Critical reviews in eukaryotic gene expression
• 影响因子: 1.6
• 作者: Bidwell,JosephP;Childress,Paul;Alvarez,MartaB;HoodJr,Mark;He,Yongzheng;Pavalko,FredrickM;Kacena,MelissaA;Yang,Feng-Chun
• 通讯作者: Yang,Feng-Chun

Nmp4/CIZ inhibits mechanically induced beta-catenin signaling activity in osteoblasts.

• DOI: 10.1002/jcp.22057
• 发表时间: 2010-05
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Yang, Zhouqi;Bidwell, Joseph P.;Young, Suzanne R.;Gerard-O'Riley, Rita;Wang, Haifang;Pavalko, Fredrick M.
• 通讯作者: Pavalko, Fredrick M.

Nmp4/CIZ: road block at the intersection of PTH and load.

• DOI: 10.1016/j.bone.2009.09.014
• 发表时间: 2010-02
• 期刊: BONE
• 影响因子: 4.1
• 作者: Childress, Paul;Robling, Alexander G.;Bidwell, Joseph P.
• 通讯作者: Bidwell, Joseph P.

RAGE supports parathyroid hormone-induced gains in femoral trabecular bone.

RAGE 支持甲状旁腺激素诱导的股骨小梁骨增加。

• DOI: 10.1152/ajpendo.00564.2009
• 发表时间: 2010
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Philip,BinuK;Childress,PaulJ;Robling,AlexanderG;Heller,Aaron;Nawroth,PeterP;Bierhaus,Angelika;Bidwell,JosephP
• 通讯作者: Bidwell,JosephP