Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression*

By Tripti Gaur, C. Lengner, H. Hovhannisyan, R. Bhat, P. Bodine, B. Komm, A. Javed, A. V. van Wijnen, J. Stein, G. Stein and 1 more. Journal of Biological Chemistry, 2005

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Both activating and null mutations of proteins required for canonical WNT signaling have revealed the importance of this pathway for normal skeletal development. However, tissue-specific transcriptional mechanisms through which WNT signaling promotes the differentiation of bone-forming cells have yet to be identified. Here, we address the hypothesis that canonical WNT signaling and the bone-related transcription factor RUNX2/CBFA1/AML3 are functionally linked components of a pathway required for the onset of osteoblast differentiation. Our findings show that, in bone of the SFRP1 (secreted frizzled-related protein-1)-null mouse, which exhibits activated WNT signaling and a high bone mass phenotype, there is a significant increase in expression of T-cell factor (TCF)-1, Runx2, and the RUNX2 target gene osteocalcin. We demonstrate by mutational analysis that a functional TCF regulatory element responsive to canonical WNT signaling resides in the promoter of the Runx2 gene (–97 to –93). By chromatin immunoprecipitation, recruitment of β-catenin and TCF1 to the endogenous Runx2 gene is shown. Coexpression of TCF1 with canonical WNT proteins resulted in a 2–5-fold activation of Runx2 promoter activity and a 7–8-fold induction of endogenous mRNA in mouse pluripotent mesenchymal and osteoprogenitor cells. This enhancement was abrogated by SFRP1. Taken together, our results provide evidence for direct regulation of Runx2 by canonical WNT signaling and suggest that Runx2 is a target of β-catenin/TCF1 for the stimulation of bone formation. We propose that WNT/TCF1 signaling, like bone morphogenetic protein/transforming growth factor-β signaling, activates Runx2 gene expression in mesenchymal cells for the control of osteoblast differentiation and skeletal development.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ad5411036b37baaf2fc22fcc98525892fc5bf42e

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Citations in the corpus

Effects of dexamethasone, ascorbic acid and β-glycerophosphate on the osteogenic differentiation of stem cells in vitro (2013, background): “Previously, other groups demonstrated that canonical Wnt signaling promotes osteoblast differentiation, in part through Runx2 expression [15].”
Inflammatory bone loss: pathogenesis and therapeutic intervention (2012, background): “Activation of RUNX2 allows mesenchymal progenitor cells to proliferate and differentiate into preosteoblasts and subsequently into mature osteoblast”
Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation (2007, positive): “Chromatin immunoprecipitation and promoter mutational analyses showed that β-catenin/LEF (lymphoid enhancer binding factor)/TCF1 (T-cell factor 1) occupy a cognate binding site in the proximal runx2 promoter and may therefore directly regulate runx2 expression [50].”
Regulation of osteoblast differentiation by transcription factors (2006, background): “Further, b-catenin/TCF1 enhances Runx2 expression and Runx2 promoter activity [Gaur et al., 2005].”
Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2 (2019, background): “the P1 promoter and osteoblast-specific enhancer of Runx2 [14,26,47,48].”
The control of chondrogenesis (2006, background): “Recent reports from several groups indicate that Wnt signaling, via the canonical b-catenin pathway and activation of TCF/Lef transcription factors, functions in a cell autonomous manner to induce osteoblast differentiation and suppress chondrocyte differentiation in early chondroprogenitors [Day et”
Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors (2006, background): “Canonical Wnt ligands have been shown to stimulate Runx2 expression and Runx2 is itself essential for osteoblast development (Gaur et al., 2005).”