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Comprehensive gene expression analysis during chondrogenesis from progenitor cells, ,and application of this technique to tissue repair

祖细胞软骨形成过程中的综合基因表达分析，以及该技术在组织修复中的应用

基本信息

批准号：
16390436
负责人：
WAKITANI Shigeyuki
金额：
$ 8.15万
依托单位：
Osaka City University (2006-2007)Shinshu 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 2007
项目状态：
已结题

项目摘要

Articular cartilage defects are a major clinical problem for orthopaedic surgeons. Autologous chondrocyte implantation (ACI) was explored, and performed in more than 20,000 patients worldwide. However, the effectiveness of ACI remains controversial due to a lack of evidence of efficacy from randomized controlled trials. There is currently no satisfactory clinical technique that is widely accepted for the regenerative repair of these lesions.We have been interested in the use of bone marrow mesenchymal cells (BMMC) because they have a number of suitable properties Therefore, this procedure can be performed clinically with relative ease. Thus, we performed BMMC transplantation in human articular cartilage defects in knee joints. Although the clinical results was good, the repair tissue was not hyaline cartilage, but fibrous cartilage. We thought that promotion of chondrogenic differentiation is very important not only in science but also in clinical practice.We have reported that recombi … More nant human Bmp2 (rhBMP-2) could induce the differentiation of muscle-derived mesenchymal cells into chondrocytes and form cartilage tissue in a diffusion chamber. Since this diffusion chamber system can separate transplanted cells from host tissue and prevent host cell contamination (neovascularization and immune system infiltration), we attempted to identify the genes that regulate chondrocyte differentiation in this system by gene expression profile using GeneChip. Although gene expression profiles of chondrocyte differentiation were reported, the combination with a diffusion chamber system can be more powerful tool for the detailed analysis of the chondrocyte .differentiation. We identified many up-regulated genes in this chondrogenic system. We selected 20 transcriptional factor and within them 10 genes were up-regulated in the early phase of chondrogenesis and the suppression of some genes using RNA interference (RNAi) revealed the association of these genes with chondrogenesis. KLF9, which suppressed most, was transfected into undifferentiated mesenchymal cells, but the chondrogenic differentiation was not promoted. It is suggested that KLF9 needed co-factors. Less

关节软骨缺损是困扰骨科医生的主要临床问题。自体软骨细胞植入（ACI）被探索，并在全球超过20,000例患者中进行。然而，由于缺乏随机对照试验的有效性证据，ACI的有效性仍然存在争议。目前还没有令人满意的临床技术被广泛接受用于这些病变的再生修复。我们一直对骨髓间充质细胞（BMMC）的使用感兴趣，因为它们具有许多合适的特性，因此，该程序可以相对容易地在临床上进行。因此，我们对人膝关节关节软骨缺损进行BMMC移植。虽然临床效果良好，但修复组织不是透明软骨，而是纤维软骨。我们认为促进软骨分化不仅在科学上很重要，而且在临床实践中也很重要。我们已经报道了重组人Bmp2 （rhBMP-2）可以诱导肌源性间充质细胞向软骨细胞分化，并在扩散室中形成软骨组织。由于这个扩散室系统可以将移植细胞从宿主组织中分离出来，并防止宿主细胞污染（新生血管和免疫系统浸润），我们试图利用基因芯片通过基因表达谱鉴定该系统中调节软骨细胞分化的基因。虽然已有关于软骨细胞分化的基因表达谱的报道，但与扩散室系统的结合可以更有力地分析软骨细胞的分化。我们在这个软骨形成系统中发现了许多上调基因。我们选择了20个转录因子，其中10个基因在软骨形成的早期阶段被上调，使用RNA干扰（RNAi）抑制一些基因揭示了这些基因与软骨形成的关联。将抑制作用最大的KLF9转染到未分化的间充质细胞中，但未促进成软骨分化。提示KLF9需要辅助因子。少