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Bone morphogenetic protein‐2 enhances Wnt/β‐catenin signaling‐induced osteoprotegerin expression
Author(s) -
Sato Mari M.,
Nakashima Aiko,
Nashimoto Masayuki,
Yawaka Yasutaka,
Tamura Masato
Publication year - 2009
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2008.01258.x
Subject(s) - wnt signaling pathway , beta catenin , dkk1 , biology , osteoprotegerin , signal transduction , microbiology and biotechnology , lrp5 , gsk 3 , bone morphogenetic protein , lrp6 , cancer research , activator (genetics) , receptor , gene , biochemistry
Wnt/β‐catenin signaling plays an important role in the developing skeletal system. Our previous studies demonstrated that Wnt/β‐catenin signaling inhibits the ability of bone morphogenetic protein (BMP)‐2 to suppress myotube formation in the multipotent mesenchymal cell line C2C12 and that this inhibition is mediated by Id1. In this study, we examined the role of intracellular signaling by Wnt/β‐catenin and BMP‐2 in regulating the expression of osteoprotegerin (OPG) and of the receptor activator of NFκB ligand (RANKL). OPG expression was induced by Wnt/β‐catenin signaling in C2C12 cells and osteoblastic MC3T3‐E1 cells. Silencing of glycogen synthase kinase‐3β also increased OPG expression. In contrast, R expression was suppressed by Wnt/β‐catenin signaling. In a transfection assay, β‐catenin induced the activity of a reporter gene, a 1.5 kb fragment of the 5′‐flanking region of the OPG gene. Deletion and mutation analysis revealed that Wnt/β‐catenin signaling regulates transcription of OPG via a promoter region containing two Wnt/β‐catenin responsive sites. BMP‐2 enhanced Wnt/β‐catenin‐dependent transcriptional activation of the OPG promoter. In response to BMP‐2 stimulation, Smad 1 and 4 interacted with Wnt/β‐catenin responsive sites. These results show that the regulation of OPG expression is mediated through two transcription pathways that involve the OPG promoter.