The mechanism of transcriptional regulation of Runx2 gene and the program of skeletal development

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Runx2 is an essential transcription factor for osteoblast differentiation at an early stage and chondrocyte differentiation at a late stage. To elucidate the mechanism of the transcriptional regulation of Runx2 gene, we generated GFP transgenic mice using the BAC clone of Runx2 gene locus. By deleting the BAC clone, we identified osteoblast-specific enhancer. The enhancer directed GFP expression specifically to osteoblasts. Dlx5/Dlx6, Mef2, Tcf7, Ctnnb1, Sp7, Smad1, and Sox5/Sox6, which localized on the enhancer region, synergistically upregulated the enhancer activity. Dlx5 and Mef2 directly bound to the enhancer, while the other factors bound to the enhancer by protein-protein interaction. Thus, Dlx5/Dlx6 and Mef2, which formed an enhanceosome with Tcf7, Ctnnb1, Sp7, Smad1, and Sox5/Sox6, play an essential role in the osteoblast-specific activation of the enhancer, leading to the differentiation of mesenchymal stem cells to osteoblasts.