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Analysis of regulatory mechanisms of bone metabolism utilizing TAK1-conditional knockout mice

TAK1条件敲除小鼠骨代谢调控机制分析

基本信息

批准号：
16390434
负责人：
SATO Kojiro
金额：
$ 8.19万
依托单位：
Saitama Medical University (2006)Tokyo Medical and Dental University (2004-2005)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

Osteoclasts are specially differentiated multinucleated macrophages that resorb bone matrix. Their function is essential for normal bone metabolism ; their dysfunction causes osteopetrosis and their hyper-function can lead to osteoporosis or bone destruction observed in rheumatoid arthritis. Thus, it is important to understand the mechanisms of their differentiation and functions.We previously reported that a transcription factor NFATc1 is strongly induced in the course of osteoclastogenesis in vitro. During the period covered by this grant, we showed that (1) NFATc1 is indeed required for osteoclastogenesis in vivo and that (2) one of immunoreceptors, OSCAR, is a target of NFATc1 whilst it is involved in activation of NFATc1, thus constituting a novel positive feedback system. We also discovered a novel T helper cell subset, now called Th17 cells, which can enhance osteoclastogenesis. Th1 and Th2 cells strongly suppressed osteoclastogenesis, casting doubt on the notion that rheumatoid … More arthritis (RA), in which bone destruction is one of the characteristics, is a Th1 disease. IL-17 that is produced by Th17 cells and IL-23 that is required for Th17 cell expansion could be promising targets for the treatment of RA. Finally, we found that calcium/calmodulin-dependent kinases (CaMKs) are involved in osteoclastogenesis. Among them, we showed through knockdown experiments that CaMKIV is especially important. In fact, CaMKIV KO mice showed increased bone mass (osteopetrosis) because of reduced osteoclastogenesis. The molecular target of CaMKIV seems to be a transcription factor CREB, which is required for NFATc1 induction, because forced expression of constitutive active CREB can rescue osteoclast differentiation in the presence of CaMK inhibitor in vitro. In mouse models bone destruction (an LPS injection model) and osteoporosis (an ovariectomy model), the CaMK inhibitor ameriolated both of the diseases. Thus, CaMK-CREB pathway is also a promising target in the treatment of bone diseases. Less

破骨细胞是特殊分化的多核巨噬细胞，吸收骨基质。它们的功能对于正常的骨代谢是必不可少的;它们的功能障碍导致骨硬化症，并且它们的功能亢进可导致骨质疏松症或在类风湿性关节炎中观察到的骨破坏。因此，了解其分化和功能的机制是非常重要的。我们以前报道过，在体外破骨细胞形成过程中，转录因子NFATc 1被强烈诱导。在本研究期间，我们发现（1）NFATc 1确实是体内破骨细胞生成所必需的，（2）免疫受体之一OSCAR是NFATc 1的靶点，同时它参与NFATc 1的激活，从而构成了一个新的正反馈系统。我们还发现了一种新的T辅助细胞亚群，现在称为Th 17细胞，它可以增强破骨细胞的生成。Th 1和Th 2细胞强烈抑制破骨细胞的生成，这使人们对类风湿性关节炎的概念产生了怀疑。 ...更多信息以骨破坏为特征之一的关节炎（RA）是一种Th 1型疾病。Th 17细胞产生的IL-17和Th 17细胞扩增所需的IL-23可能是治疗RA的有希望的靶点。最后，我们发现钙/钙调素依赖性激酶（CaMK）参与破骨细胞的形成。其中，我们通过敲除实验表明CaMKIV尤其重要。事实上，由于破骨细胞生成减少，CaMKIV KO小鼠显示出骨量增加（骨硬化症）。CaMKIV的分子靶点似乎是转录因子CREB，这是NFATc 1诱导所必需的，因为在体外存在CaMK抑制剂的情况下，组成型活性CREB的强制表达可以拯救破骨细胞分化。在小鼠模型骨破坏（LPS注射模型）和骨质疏松症（卵巢切除模型）中，CaMK抑制剂使这两种疾病都消失。因此，CaMK-CREB通路也是骨疾病治疗的一个有前途的靶点。少

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

活性化T細胞による破骨細胞分化制御

活化 T 细胞控制破骨细胞分化

DOI：
发表时间：
2005
期刊：
日本臨床 63(9)
影响因子：
0
作者：
Wakitani S;Ohgushi H;Machida H;Nakaya H;Murakami N;Yamasaki H;Kato H;Kawaguchi A;Okabe T;Tensho K;Sato Kojiro;Sato Kojiro;Sato Kojiro;佐藤浩二郎;Sato Kojiro;Sato Kojiro;Sato Kojiro;Kim Yoonji;Asagiri Masataka;Takayanagi Hiroshi;佐藤浩二郎;佐藤浩二郎
通讯作者：
佐藤浩二郎

CD25^+CD4^+T細胞によるCD4^+T細胞の増殖抑制機構

CD25^+CD4^+ T细胞抑制CD4^+ T细胞增殖的机制

DOI：
发表时间：
2004
期刊：
臨床免疫 42(4)
影响因子：
0
作者：
Gohda;J.;Akiyama;T.;Koga;T.;Takayanagi;H.;他2名;Sato Kojiro;佐藤浩二郎;佐藤浩二郎
通讯作者：
佐藤浩二郎

Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction.

DOI：
10.1084/jem.20061775
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Sato K;Suematsu A;Okamoto K;Yamaguchi A;Morishita Y;Kadono Y;Tanaka S;Kodama T;Akira S;Iwakura Y;Cua DJ;Takayanagi H
通讯作者：
Takayanagi H

多腺性自己免疫症候群

多腺体自身免疫综合征