Novel therapeutic approaches to bone diseases using cell cycle factors Cdk4/6

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This study aimed to develop novel therapeutic approaches to bone diseases using cell cycle factors, Cdk4/6. First, we investigated the effects of several Cdk inhibitors on osteoblast differentiation. We discovered that some Cdk inhibitors could alter osteoblast differentiation. In addition, to identify downstream molecules involved in the promotion of osteogenic differentiation by Cdk inhibition, we performed a DNA microarray analysis. From the up-regulated genes, we selected several genes as candidates which could regulate osteogenic differentiation as downstream effectors of Cdk inhibition. Among these genes, we focused on Zinc finger proteins or G protein-coupled receptors etc., in consideration of both the expression change and findings gathered from the literature. Real-time quantitative RT-PCR analyses confirmed that that there were up-regulations of some of candidate genes. Next, to investigate the functional relevance of such genes to the osteogenic differentiation promo by Cdk inhibition, we knocked down candidate genes through small RNA interference (siRNA). Moreover, we generated several double mutant mice to investigate the effects of Cdk inhibition in vivo. One of double mutant mice proved that the phenotype in some knockout mice was partially rescued by Cdk inhibition. In conclusion, the results of this study imply that the modulation of Cdks may lead to novel therapeutics to treat bone catabolic disorders.