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The role of CTGF as a novel tissue-regenerating factor, regenerin, and its application for medical and dental tissue engineering

CTGF作为新型组织再生因子再生素的作用及其在医学和牙科组织工程中的应用

基本信息

批准号：
15109010
负责人：
TAKIGAWA Masaharu
金额：
$ 66.48万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

项目摘要

1. Using wild type and/or mutant animals, we found that in addition to endochondral ossification in growth plate, CTGF/CCN2 was involved in secondary ossification center formation, intramembranous ossification, formation of periodontal ligament and articular and auricular cartilages, distraction osteogenesis and repair of tooth extraction socket. In vivo administration of CTGF/CCN2 with gelatin hydrogel into the artificial defect of articular cartilage and bone resulted in repair of these tissues, respectively. Taken together with the finding that platelets contained much CTGF/CCN2, these findings indicate that CTGF/CCN2 functions as a regeneration factor "regenerin".2. We developed CTGF/CCN2 domain-specific antibodies and domain-specific ELISA systems. The function and signal transduction pathway of each domain was different depending on types of cells, such as chondrocytes and endothelial cells. CT domain of CTGF/CCN2 promoted adhesion of mesenchymal stem cells on hydroxyapatite plates, suggesting a possible application for bone regeneration with a combination of CTGF/CCN2 and hydroxyapatite.3. A cis-element in 3'-untranslation region (3'-UTR) of CTGF/CCN2 mRNA, which was involved in destabilization of its mRNA, and a protein, which bound to the element, were found in chondrocytes. The biding between them changed in reverse relation to the process of chondrocyte differentiation. A hypoxia-inducible protein, which stabilized CTGF/CCN2 mRNA by binding to its 3'-UTR was also detected.4. CTGF/CCN2 bound to perlecan, aggrecan and fibronectin, indicating its retention in extracellular matrix. CTGF/CCN2 had collaborative action with M-CSF on cartilage. Low density lipoprotein-related protein I was one of the receptors for CTGF/CCN2 in chondrocytes. Concerning signal transduction pathway of CTGF/CCN2 in chondrocytes, PKC was found as an upstream mediator of ERK and p38MAPK. JNK was involved in cell proliferation. PI3K and PKB were found to be involved in calcification.

1. 通过野生型和/或突变型动物，我们发现CTGF/CCN2除参与生长板软骨内成骨外，还参与继发性成骨中心的形成、膜内成骨、牙周韧带和关节、耳廓软骨的形成、牵张成骨和拔牙窝的修复。在体内用明胶水凝胶将CTGF/CCN2注入人工关节软骨和骨缺损，分别修复了这两个组织。结合血小板含有大量CTGF/CCN2的发现，这些发现表明CTGF/CCN2具有再生因子“再生素”的功能。我们开发了CTGF/CCN2结构域特异性抗体和结构域特异性ELISA系统。每个结构域的功能和信号转导途径因细胞类型不同而不同，如软骨细胞和内皮细胞。CTGF/CCN2的CT结构域促进了间充质干细胞在羟基磷灰石板上的粘附，提示CTGF/CCN2与羟基磷灰石联合应用于骨再生的可能性。在软骨细胞中发现了CTGF/CCN2 mRNA 3'-非翻译区（3'-UTR）的顺式元件和与该元件结合的蛋白，该元件参与了CTGF/CCN2 mRNA的失稳。它们之间的结合与软骨细胞分化过程成反比。我们还发现了一种低氧诱导蛋白，该蛋白通过与CTGF/CCN2 mRNA的3'-UTR结合来稳定CTGF/CCN2 mRNA。CTGF/CCN2与过渗蛋白、聚集蛋白和纤维连接蛋白结合，表明其保留在细胞外基质中。CTGF/CCN2与M-CSF协同作用于软骨。低密度脂蛋白相关蛋白I是软骨细胞中CTGF/CCN2的受体之一。在CTGF/CCN2在软骨细胞中的信号转导途径中，PKC被发现是ERK和p38MAPK的上游介质。JNK参与细胞增殖。发现PI3K和PKB参与钙化。

项目成果

期刊论文数量（150）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comparable response of ccn1 with ccn2 genes upon arthritis: An in vitro evaluation with a human chondrocytic cell line stimulated by a set of cytokines.

DOI：
10.1186/1478-811x-3-6
发表时间：
2005-04-15
期刊：
Cell communication and signaling : CCS
影响因子：
0
作者：
Moritani NH;Kubota S;Sugahara T;Takigawa M
通讯作者：
Takigawa M

Collaborative action of M-CSF and CTGF/CCN2 in articular chondrocytes : possible regeneration roles in articular cartilage metabolism.

M-CSF 和 CTGF/CCN2 在关节软骨细胞中的协同作用：在关节软骨代谢中可能的再生作用。

DOI：
发表时间：
2005
期刊：
Bone 36
影响因子：
0
作者：
Yaegashi Y;Shirawawa K;Sato N;Suzuki Y;Kojika M;Imai S;Takahashi G;Miyata M;Furusako S;Endo S;Nakao K et al.
通讯作者：
Nakao K et al.

Regulation of chicken ccn2 gene by interaction between RNA cis-element and putative transfactor during differentiation of chondrocytes.

软骨细胞分化过程中，RNA 顺式元件和推定反式因子之间的相互作用对鸡 ccn2 基因的调节。