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.

doi:10.1074/jbc.m500608200

Cited by 1,170Wnt/β-catenin signaling in development and cancerBone Metabolism and DiseasesBone health and osteoporosis research

Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression

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Gaur, Tripti, Lengner, Christopher J., Hovhannisyan, Hayk, Bhat, Ramesh A., Bodine, Peter V.N., Komm, Barry S., Javed, Amjad, van Wijnen, Andre J. +3 more·2005·Journal of Biological Chemistry

DOI 10.1074/jbc.m500608200

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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 beta-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 beta-catenin/TCF1 for the stimulation of bone formation. We propose that WNT/TCF1 signaling, like bone morphogenetic protein/transforming growth factor-beta signaling, activates Runx2 gene expression in mesenchymal cells for the control of osteoblast differentiation and skeletal development.

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β-catenin is required for bone formation and is activated during multiple stages of osteoblast differentiation to regulate both osteoblast and osteoclast.
“Many studies have demonstrated that β-catenin is required for bone formation and is activated during multiple stages of osteoblast differentiation to regulate both osteoblast and osteoclast.40–43”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [43]

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Authors: Gaur, T., Lengner, C. J., Hovhannisyan, H., Bhat, R. A., Bodine, P. V. N., Komm, B. S., Javed, A., van Wijnen, A. J., Stein, J. L., Stein, G. S., & Lian, J. B.
Affiliations: University of Massachusetts Chan Medical School (US)
Wyeth (US)
Corresponding author: Lian, Jane B.
ORCID: Lengner, Christopher J.
Hovhannisyan, Hayk
Javed, Amjad
Stein, Janet L.
Stein, Gary S.
Lian, Jane B.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2005-09
Volume: 280
Issue: 39
Pages: 33132-33140
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m500608200
OpenAlex: W2153720415
Cited by: 1,170
References: 70
Citations by year: 2026: 32 · 2025: 40 · 2024: 43 · 2023: 46 · 2022: 64 · 2021: 80 · 2020: 96 · 2019: 68 · 2018: 56 · 2017: 73 · 2016: 65 · 2015: 74 · 2014: 57 · 2013: 67 · 2012: 55
FWCI: 13.80
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5511 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (P30DK032520, P30-DK32520)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR049069, P01 AR 48818, P01AR048818, AR 39588, R01AR039588)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords: Wnt/β-catenin signaling, Runx2, bone formation, osteogenic differentiation, SFRP1, TCF1, β-catenin, osteocalcin, skeletal development, mesenchymal cells, osteoprogenitor cells
MeSH terms: Secreted Frizzled-Related Proteins, Animals, Cell Differentiation, Cells, Cultured, Fibroblasts, Membrane Proteins, Mice, Transgenic, Models, Biological, Osteoblasts, Osteogenesis, Promoter Regions, Genetic, RNA, Messenger, Signal Transduction, Gene Expression Regulation, Developmental, Intercellular Signaling Peptides and Proteins, Chromatin Immunoprecipitation, Core Binding Factor Alpha 1 Subunit, Mice, Hepatocyte Nuclear Factor 1-alpha, Mesenchymal Stem Cells

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Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression

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