Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression

Tripti Gaur, Christopher J. Lengner, Hayk Hovhannisyan, Ramesh A. Bhat, Peter V N Bodine, Barry S. Komm, Amjad Javed, Andre J van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)33132-33140
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number39
DOIs
StatePublished - Sep 30 2005
Externally publishedYes

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Osteogenesis
Gene expression
Gene Expression
Bone and Bones
Catenins
Bone
Osteoblasts
T Cell Transcription Factor 1
Genes
TCF Transcription Factors
Bone Morphogenetic Proteins
Chromatin Immunoprecipitation
Osteocalcin
Transforming Growth Factors
Proteins
Transcription Factors
Messenger RNA
Mutation
Chromatin
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Gaur, T., Lengner, C. J., Hovhannisyan, H., Bhat, R. A., Bodine, P. V. N., Komm, B. S., ... Lian, J. B. (2005). Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. Journal of Biological Chemistry, 280(39), 33132-33140. https://doi.org/10.1074/jbc.M500608200

Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. / Gaur, Tripti; Lengner, Christopher J.; Hovhannisyan, Hayk; Bhat, Ramesh A.; Bodine, Peter V N; Komm, Barry S.; Javed, Amjad; van Wijnen, Andre J; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.

In: Journal of Biological Chemistry, Vol. 280, No. 39, 30.09.2005, p. 33132-33140.

Research output: Contribution to journalArticle

Gaur, T, Lengner, CJ, Hovhannisyan, H, Bhat, RA, Bodine, PVN, Komm, BS, Javed, A, van Wijnen, AJ, Stein, JL, Stein, GS & Lian, JB 2005, 'Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression', Journal of Biological Chemistry, vol. 280, no. 39, pp. 33132-33140. https://doi.org/10.1074/jbc.M500608200
Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. Journal of Biological Chemistry. 2005 Sep 30;280(39):33132-33140. https://doi.org/10.1074/jbc.M500608200
Gaur, Tripti ; Lengner, Christopher J. ; Hovhannisyan, Hayk ; Bhat, Ramesh A. ; Bodine, Peter V N ; Komm, Barry S. ; Javed, Amjad ; van Wijnen, Andre J ; Stein, Janet L. ; Stein, Gary S. ; Lian, Jane B. / Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 39. pp. 33132-33140.
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