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Proc Natl Acad Sci U S A
2008 May 13;10519:6936-41. doi: 10.1073/pnas.0710831105.
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Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix.
Zhang C
,
Cho K
,
Huang Y
,
Lyons JP
,
Zhou X
,
Sinha K
,
McCrea PD
,
de Crombrugghe B
.
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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 beta-catenin-induced Topflash reporter activity and beta-catenin-induced secondary axis formation in Xenopus embryos. Importantly, in calvaria of E18.5 Osx-null embryos harboring the TOPGAL reporter transgene, beta-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 beta-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/beta-catenin activity. Our results add a layer of control to Wnt/beta-catenin signaling in bone.
Fig. 5.
Inhibition of β-catenin transcription activity by Osx. (A) Osx inhibits β-catenin-induced Wnt reporter activity. HEK293 cells were transfected with the Topflash or Fopflash reporter along with Myc-β-catenin, a plasmid expressing a stabilized β-catenin, and increasing amounts of pEX-Osx DNA. (B) Osx inhibits β-catenin-induced secondary axis formation in Xenopus embryos. Embryos were microinjected with RNA for stabilized β-catenin (100 pg) and increasing amounts of Osx RNA at the four-cell cleavage stage into the equatorial region of a single vegetal-ventralblastomere. Microinjection of β-catenin RNA in the ventral side of four-cell Xenopus embryos induces the formation of a secondary body axis. The phenotypes were evaluated by using a binocular dissecting microscope at the tadpole stage. (C) Dose-dependent inhibition of β-catenin-induced secondary axis formation in Xenopus embryos by Osx. (D) β-galactosidase activity in calvarial extracts of E18.5 Osx+/+;TOPGAL and Osx−/−;TOPGAL embryos. Results were expressed as the ratio of β- galactosidase over DNA.
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