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

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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.