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Conserved regulatory motifs in osteogenic gene promoters integrate cooperative effects of canonical Wnt and BMP pathways
Author(s) -
RodríguezCarballo Edgardo,
Ulsamer Arnau,
Susperregui Antonio RG,
ManzanaresCéspedes Cristina,
SánchezGarcía Eva,
Bartrons Ramon,
Rosa José Luis,
Ventura Francesc
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.260
Subject(s) - wnt signaling pathway , enhancer , runx2 , bone morphogenetic protein , transcription factor , biology , microbiology and biotechnology , gene , smad , promoter , bone morphogenetic protein 2 , genetics , gene expression , in vitro
Osteoblast differentiation depends on the coordinated network of evolutionary conserved transcription factors during bone formation and homeostasis. Evidence indicates that bone morphogenetic protein (BMP) and Wnt proteins regulate several steps of skeletal development. Here, we provide a molecular description of the cooperative effects of BMP and Wnt canonical pathway on the expression of the early osteogenic genes Dlx5 , Msx2 , and Runx2 in C2C12 cells, primary cultures of bone marrow–mesenchymal stem cells, and organotypic calvarial cultures. Coordinated regulation of these genes leads to the cooperative activation of their downstream osteogenic target gene osterix . Induction of these genes is mediated through enhancer regions with an evolutionary conserved structure encompassing both Smad and TCF/LEF1 DNA‐binding sites. Formation of a cooperative complex is mediated through DNA binding of Smads and TCF4/β‐catenin to their cognate sequences, as well as protein‐protein interactions between them. The formation of these cooperative transcriptional complexes results in a more efficient recruitment of coactivators such as p300. We propose that evolutionary conserved regulatory regions in specific osteogenic master genes are key integrative modules during osteogenesis. © 2011 American Society for Bone and Mineral Research.