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Sclerostin is a direct target of osteoblast-specific transcription factor osterix

Fan Yang1, Wanjin Tang, Sarah So

  • 1Bone Research Laboratory, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.

Biochemical and Biophysical Research Communications
|September 7, 2010
PubMed

Insights

Osterix (Osx) directly activates Sclerostin (Sost) gene expression, revealing a new mechanism for how Osx regulates Wnt signaling and bone formation.

Area of Science:

  • Molecular Biology
  • Bone Biology
  • Cell Signaling

Background:

  • Osterix (Osx) is crucial for osteoblast differentiation and bone formation.
  • Osx regulates Wnt signaling, a key pathway in bone metabolism.
  • The precise mechanisms of Osx's inhibition of Wnt signaling are not fully elucidated.

Purpose of the Study:

  • To investigate the regulatory relationship between Osterix (Osx) and Sclerostin (Sost).
  • To identify the molecular mechanisms by which Osx influences Wnt signaling through Sost.

Main Methods:

  • Analysis of Sost expression in Osx-null and Osx-overexpressing cells.
  • Reporter assays using Sost promoter deletion mutants.
  • Gel shift and point mutation analyses to identify Osx binding sites.
  • Chromatin immunoprecipitation (ChIP) assays in primary osteoblasts.

Main Results:

  • Sclerostin (Sost) expression was downregulated in Osx-deficient bone and upregulated upon Osx overexpression.
  • Osx directly activated the Sost promoter, with the minimal activating region identified within 260bp.
  • Osx binds to a specific GC-rich site in the Sost promoter, which is essential for activation.
  • ChIP assays confirmed Osx binding to the endogenous Sost promoter in vivo.

Conclusions:

  • Sclerostin (Sost) is a direct transcriptional target of Osterix (Osx).
  • Osx activates Sost expression by binding to a specific site in its proximal promoter.
  • This Osx-Sost interaction provides a novel mechanism for Osx-mediated inhibition of Wnt signaling in bone formation.

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