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An exploratory research for prevention of chondrocyte dedifferentiation and treatment for osteoarthritis through the regulation of integrin actitivy

通过整合素活性调节预防软骨细胞去分化和治疗骨关节炎的探索性研究

基本信息

批准号：
18390424
负责人：
FUKUI Naoshi
金额：
$ 10.96万
依托单位：
Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390424/
关键词：
Chondrocte Dedifferentiation Integrin Cartilage tissue engineering Osteoarthritis ERK

项目摘要

Articular chondrocytes are known to undergo dedifferentiation when liberated from the surrounding matrix and maintained in monolayer. During the process of dedifferentiation, the change of cell morphology and pattern of gene expression occurs in parallel. Although this is a well known phenomenon, the mechanism(s) that promotes the process has not been determined. In an attempt to elucidate the mechanism, we performed RNAi for respective integrins expressed in human articular chondrocytes, and found that two sets of integrin heterodimers, α5β1 and αvβ5, are responsible for the progression of that process. The results of our research indicated that these heterodimers promote respective aspects of the process through the activation of AKT and ERK signal pathways. After plating, dedifferentiation occurs gradually, taking several days to weeks to complete the process. Then we farther attempted to determine the mechanism(s) for the gradual progression, and found that the time course could be explained by the gradual activation of α5β1 and αvβ5 by RRAS, a small GTPase known to regulate integrin activation.We next applied our findings to maintain the phenotype of cultured chondrocytes. Human articular chondorcytes were maintained in pellets in the presence or absence of echistatin, a distintegrin that potently inhibits integrin activation. The result of this experiment revealed that the inhibition of integrin activation in fact prevented phenotypic change of the chondrocytes. Our result could be helpful when cartilage regeneration is attempted to treat patients with osteoarthritis and cartilage injury.

已知关节软骨细胞从周围基质中释放出来并维持在单层时经历去分化。在去分化过程中，细胞形态和基因表达模式的变化是平行发生的。虽然这是一个众所周知的现象，但促进这一过程的机制尚未确定。为了阐明其机制，我们对人关节软骨细胞中表达的相应整合素进行了RNAi，发现两组整合素异二聚体α5β1和αvβ5负责该过程的进展。我们的研究结果表明，这些异二聚体通过激活AKT和ERK信号通路促进该过程的各个方面。接种后，去分化逐渐发生，需要数天至数周才能完成该过程。然后我们进一步尝试确定渐进性进展的机制，并发现时间过程可以通过RRAS（一种已知调节整合素激活的小GT酶）逐渐激活α5β1和αvβ5来解释。我们接下来将我们的发现应用于维持培养软骨细胞的表型。人关节软骨细胞在存在或不存在echistatin（一种有效抑制整合素活化的去整合素）的情况下保持在颗粒中。该实验的结果表明，抑制整联蛋白活化实际上阻止了软骨细胞的表型变化。我们的研究结果可能有助于尝试软骨再生治疗骨关节炎和软骨损伤患者。