Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression
Authors
Gaur, TriptiLengner, 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.
Student Authors
Christopher J. LengnerUMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2005-07-27Keywords
Animals; Cell Differentiation; Cells, Cultured; Chromatin Immunoprecipitation; Core Binding Factor Alpha 1 Subunit; Fibroblasts; *Gene Expression Regulation, Developmental; Hepatocyte Nuclear Factor 1-alpha; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Mesenchymal Stem Cells; Mice; Mice, Transgenic; Models, Biological; Osteoblasts; Osteogenesis; Promoter Regions (Genetics); RNA, Messenger; *Signal TransductionCell Biology
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 2005 Sep 30;280(39):33132-40. Epub 2005 Jul 25. Link to article on publisher's siteDOI
10.1074/jbc.M500608200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33727PubMed ID
16043491Related Resources
Link to article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M500608200