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 [1]. A recent study [2] reports that the osteoblast-specific transcription factor Osterix (Osx), which is required for osteoblast differentiation, inhibits Wnt pathway activity. In calvarial cells of 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, these studies demonstrated that Osx bound to and activated the Dkk1 promoter. In addition, Osx inhibited β-catenin-induced reporter activity and β-catenin-induced secondary axis formation in Xenopus embryos. Importantly, data from calvaria of Osx-null embryos indicate that Osx inhibited the Wnt pathway in osteoblasts in vivo. This study further shows that Osx disrupts binding of transcription factor TCF to DNA. This provides a likely mechanism for the inhibition by Osx of β-catenin transcriptional activity. Osx decreased also osteoblast proliferation. Indeed, Osx-null calvaria showed greater BrdU incorporation than wild-type calvaria and Osx overexpression in C2C12 mesenchymal cells inhibited cell growth. Because Wnt signaling has a major role in stimulating osteoblast proliferation, the authors speculate that Osx-mediated inhibition of osteoblast proliferation is a consequence of the Osx-mediated control of Wnt/β-catenin activity.

1. Piters E et al. Arch Biochem Biophys. 2008;473:112-116.
2. Zhang C et al. Proc Natl Acad Sci USA. 2008;105:6936–6941.