The transcription factor snail regulates osteogenic differentiation by repressing Runx2 expression

Osteoblasts originate from mesenchymal stem cells by the coordinated activities of different signaling pathways that regulate the expression of osteoblast-specific genes. Runt-related transcription factor 2 (Runx2) is the master transcription factor for osteoblast differentiation. Despite the importance of Runx2 in the developing skeleton, how Runx2 expression is regulated remains a pivotal question. Snail, a zinc finger transcription factor, is essential for triggering epithelial-to-mesenchymal transitions (EMTs) during embryonic development and tumor progression. Here, we report that Runx2 expression is significantly up- or down-regulated relative to Snail expression. We demonstrate that Snail binds to the Runx2 promoter and that repression of Runx2 transcription by Snail is dependent on specific E-box sequence within the promoter. With antisense morpholino oligonucleotide (MO)-mediated knockdown of Snail expression in zebrafish, we observed alterations in osteogenic potential. These results indicate that Snail plays a crucial role in osteogenic differentiation by acting as a direct Runx2 repressor.This work was supported by the Science Research Center grant to Bone Metabolism Research Center (2009-0063265) funded by the Korean Ministry of Education, Science and Technology. This work was also supported by the Brain Korea 21 Project for Medical Science, Yonsei University. Kim CH was supported by grant FG09-42-1 of the 21C Frontier Functional Human Genome Project from the Ministry of Science & Technology in Korea