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Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix

Author:
Zhang, Chi, Cho, Kyucheol, Huang, Yehong, Lyons, Jon P., Zhou, Xin, Sinha, Krishna, McCrea, Pierre D., de Crombrugghe, Benoit
Source:
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.19 pp. 6936-6941
ISSN:
0027-8424
Subject:
DNA, Xenopus, animal models, antagonists, beta-galactosidase, bone density, cell growth, cyclins, genetic disorders, homeostasis, humans, osteoblasts, transcription (genetics), transcription factors, transgenes
Abstract:
The recent identification of the genes responsible for several human genetic diseases affecting bone homeostasis and the characterization of mouse models for these diseases indicated that canonical Wnt signaling plays a critical role in the control of bone mass. Here, we report that the osteoblast-specific transcription factor Osterix (Osx), which is required for osteoblast differentiation, inhibits Wnt pathway activity. First, in calvarial cells of embryonic day (E)18.5 Osx-null embryos, expression of the Wnt antagonist Dkk1 was abolished, and that of Wnt target genes c-Myc and cyclin D1 was increased. Moreover, our studies demonstrated that Osx bound to and activated the Dkk1 promoter. In addition, Osx inhibited β-catenin-induced Topflash reporter activity and β-catenin-induced secondary axis formation in Xenopus embryos. Importantly, in calvaria of E18.5 Osx-null embryos harboring the TOPGAL reporter transgene, β-galactosidase activity was increased, suggesting that Osx inhibited the Wnt pathway in osteoblasts in vivo. Our data further showed that Osx disrupted binding of Tcf to DNA, providing a likely mechanism for the inhibition by Osx of β-catenin transcriptional activity. We also showed that Osx decreased osteoblast proliferation. Indeed, E18.5 Osx-null calvaria showed greater BrdU incorporation than wild-type calvaria and that Osx overexpression in C2C12 mesenchymal cells inhibited cell growth. Because Wnt signaling has a major role in stimulating osteoblast proliferation, we speculate that Osx-mediated inhibition of osteoblast proliferation is a consequence of the Osx-mediated control of Wnt/β-catenin activity. Our results add a layer of control to Wnt/β-catenin signaling in bone.
Agid:
2361359