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. 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. During development of the skeleton and formation of bone tissue, several morphogenic growth factor and hormone signaling pathways impinge upon transcriptional regulators to induce the osteogenic phenotype (1Karaplis A. Bilezikian J.P. Raisz L.G. Rodan G.A. Principles of Bone Biology. Academic Press, Inc., San Diego, CA2002: 33-58Google Scholar, 2Lian J.B. Stein G.S. Aubin J.E. Favus M.J. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. American Society for Bone and Mineral Research, Washington, D. C.2003: 13-28Google Scholar). The challenge is to identify how developmental cues and regulatory factors are integrated to accommodate the requirements for biological control of cell differentiation and tissue formation. Here, we have addressed the interaction of two key signals for osteogenesis: the WNT pathway, which contributes to the development of skeletal structures (3Church V.L. Francis-West P. Int. J. Dev. Biol. 2002; 46: 927-936PubMed Google Scholar, 4Westendorf J.J. Kahler R.A. Schroeder T.M. Gene (Amst.). 2004; 341: 19-39Crossref PubMed Scopus (677) Google Scholar), and the transcription factor RUNX2 (CBFA1/AML3), which is required for embryonic bone formation (5Komori T. J. Cell. Biochem. 2005; 95: 445-453Crossref PubMed Scopus (274) Google Scholar, 6Kobayashi T. Kronenberg H. Endocrinology. 2005; 146: 1012-1017Crossref PubMed Scopus (137) Google Scholar). WNT signaling comprises a family of 19 secreted glycoproteins that have functions related to cell specification, formation of the body plan, cell growth, differentiation and apoptosis (7Pandur P. Maurus D. Kuhl M. BioEssays. 2002; 24: 881-884Crossref PubMed Scopus (168) Google Scholar, 8Logan C.Y. Nusse R. Annu. Rev. Cell Dev. Biol. 2004; 20: 781-810Crossref PubMed Scopus (4239) Google Scholar). WNT proteins function through Frizzled receptors, which transduce the signal through either the canonical β-catenin pathway or non-canonical pathway (7Pandur P. Maurus D. Kuhl M. BioEssays. 2002; 24: 881-884Crossref PubMed Scopus (168) Google Scholar, 8Logan C.Y. Nusse R. Annu. Rev. Cell Dev. Biol. 2004; 20: 781-810Crossref PubMed Scopus (4239) Google Scholar). Activation of the Frizzled receptor complex results in inhibition of a phosphorylation cascade that stabilizes intracellular β-catenin levels. β-Catenin is subsequently translocated to the nucleus to form a transcriptionally active heterodimeric β-catenin TCF 2The abbreviations used are: TCF, T-cell factor; LEF, lymphoid enhancer factor; BMP, bone morphogenetic protein; MEF, mouse embryonic fibroblast; WT, wild-type; RT, reverse transcription; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. lymphoid enhancer factor (LEF) DNA-binding complex. Both gain- and loss-of-function mutations in canonical and non-canonical WNT signaling components have revealed critical requirements of WNT proteins for normal skeletogenesis (3Church V.L. Francis-West P. Int. J. Dev. Biol. 2002; 46: 927-936PubMed Google Scholar, 4Westendorf J.J. Kahler R.A. Schroeder T.M. Gene (Amst.). 2004; 341: 19-39Crossref PubMed Scopus (677) Google Scholar). Altered expression of several WNT proteins (WNT3a, WNT4, WNT5a, WNT7a, and WNT14/9a) causes defects in somite formation, chondrogenesis, limb development, and endochondral bone formation (9Ikeya M. Takada S. Mech. Dev. 2001; 103: 27-33Crossref PubMed Scopus (124) Google Scholar, 10Hartmann C. Tabin C.J. Cell. 2001; 104: 341-351Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 11Hartmann C. Tabin C.J. Development (Camb.). 2000; 127: 3141-3159Crossref PubMed Google Scholar, 12Yamaguchi T.P. Bradley A. McMahon A.P. Jones S. Development (Camb.). 1999; 126: 1211-1223PubMed Google Scholar, 13Adamska M. MacDonald B.T. Sarmast Z.H. Oliver E.R. Meisler M.H. Dev. Biol. 2004; 272: 134-144Crossref PubMed Scopus (54) Google Scholar). Recently, a rare human genetic disorder (tetra-amaelia) characterized by absence of all limbs has been linked to mutation in Wnt3 (14Niemann S. Zhao C. Pascu F. Stahl U. Aulepp U. Niswander L. Weber J.L. Muller U. Am. J. Hum. Genet. 2004; 74: 558-563Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). More direct effects mediated through canonical WNT signaling on formation and turnover of the mature skeleton have been revealed. An activating mutation in the WNT coreceptor LRP5 (low density lipoprotein receptor-related protein-5) results in the high bone mass trait in humans (15Boyden L.M. Mao J. Belsky J. Mitzner L. A. D. J. 2002; PubMed Scopus Google Scholar, J. 2002; PubMed Scopus Google Scholar), a phenotype that is in the mouse P. F. Bone 2004; PubMed Scopus Google Scholar, P. Zhao C. J. R.A. F. J. Bone PubMed Scopus Google Scholar). with this phenotype, the LRP5 loss-of-function mutation exhibits and bone mass in humans S. H. T. D. M. J. S. S. J. M. P. L.M. C. A. T. A. H. A. D. M. T. L. M. H. A. M.J. M. M. T. R. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google and in a mouse M. R. C. L. R.A. L. J. Cell Biol. 2002; PubMed Scopus Google Scholar). of of the canonical WNT in to osteoblast differentiation and F. J.E. Development (Camb.). 2005; PubMed Scopus (274) Google Scholar). of the mouse H. L. M. L. R. Development (Camb.). PubMed Google Scholar), of skeletal structures the R. S. M. McMahon A.P. L. R. Development (Camb.). 2001; Google Scholar), and of osteoblast differentiation L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, T.P. D. C. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google in β-catenin mouse T. J. T. F. S. M. M. M. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google demonstrate the importance of the canonical WNT pathway developmental and for bone formation. The WNT pathway is by several secreted frizzled-related proteins which a for interaction with WNT with the receptor Frizzled coreceptor R. J. Cell PubMed Scopus Google Scholar). null mutation of the WNT SFRP1 in mouse results in high bone mass the of and Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google Scholar), effects by either SFRP1 or WNT proteins in the bone mass of the a of the transcription factor is for osteoblast differentiation (5Komori T. J. Cell. Biochem. 2005; 95: 445-453Crossref PubMed Scopus (274) Google Scholar, 6Kobayashi T. Kronenberg H. Endocrinology. 2005; 146: 1012-1017Crossref PubMed Scopus (137) Google Scholar, C. Stein J.L. Stein G.S. J.B. J. Cell. Biochem. PubMed Scopus Google Scholar, P. R. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). in the Runx2 gene in mouse and human are with and critical defects in bone formation T. H. S. A. M. M. R. S. T. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, F. A.P. T. A. S. M.J. Cell. S. Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. L. S. J.B. Stein J.L. Jones Stein G.S. U. S. A. 2001; PubMed Scopus Google Scholar, F. H. S. Hum. 2002; PubMed Scopus Google Scholar, T. H. M. M. T. PubMed Scopus Google Scholar). RUNX2 functions a regulatory in by with a of proteins and that RUNX2 a or on target cell differentiation T. Kronenberg H. Endocrinology. 2005; 146: 1012-1017Crossref PubMed Scopus (137) Google Scholar, J.B. A. C. M. Stein J.L. Stein G.S. Rev. Gene 2004; PubMed Google Scholar, R. F. A. J. J.B. Stein G.S. Stein J.L. M. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar). factors signaling morphogenetic signals and the by for with of bone morphogenetic growth factor-β signaling, and with intracellular proteins that transduce signaling F. J. Stein J.L. Stein G.S. J.B. A. J. Cell. 2005; PubMed Scopus Google Scholar, Stein J.L. Stein G.S. J.B. U. S. A. 2002; PubMed Scopus Google Scholar, R. Stein J.L. J.B. Stein G.S. J. 2004; PubMed Scopus Google Scholar). significant to that Runx2 be a target of WNT signaling for of the osteoblast the Runx2 gene is in the in that to skeletal to the formation of bone tissue P. R. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, F. A.P. T. A. S. M.J. Cell. S. Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. H. Stein J.L. Stein G.S. J.B. Mech. Dev. 2002; PubMed Scopus Google Scholar). induction of bone formation and osteoblast differentiation is by Runx2 gene Runx2 expression in is to C.J. H. Stein J.L. Stein G.S. J.B. Mech. Dev. 2002; PubMed Scopus Google Scholar). findings suggest that signals the osteogenic pathway are on the promoter for expression of Runx2 in embryonic development. this we show that the Runx2 gene is a direct target of the canonical WNT signaling Activation of the Runx2 promoter through a TCF was in mouse embryonic and pluripotent mesenchymal and osteoprogenitor cells in endogenous Runx2 and TCF1 in the mouse, which exhibits WNT signaling and osteoblast differentiation. We propose that direct regulation of Runx2 gene expression in by canonical WNT signaling is a factor for skeletal development and for bone mass in the the gene the control of the Runx2 promoter C.J. H. Stein J.L. Stein G.S. J.B. Mech. Dev. 2002; PubMed Scopus Google and SFRP1 and Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google used for in the of by the and was for mouse Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google Scholar, C.J. H. Stein J.L. Stein G.S. J.B. Mech. Dev. 2002; PubMed Scopus Google Scholar). Cell embryonic C.J. C. Stein J.L. Stein G.S. J.B. J. Cell. 2004; PubMed Scopus Google Scholar). was in in the of and a with was to The cells and for The cells used cells. The the cells in by for with human by Research, in American either for of activity in Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google or for by of of the was with and of and for The was by of and was osteoprogenitor pluripotent and cells used in this in in or in with and differentiation cells with the and and and cells with a of to the The mouse Runx2 promoter or the promoter of mouse and to the was used in H. R. S. A. M. Jones S. J.B. Stein J.L. Stein G.S. J. Cell. 2000; PubMed Scopus Google Scholar). The mutation in the was the the The expression for WNT proteins and TCF1 was and The gene was and the in a was to the The of was by the The cells in for promoter activity The activity was a for to activity in a of the cell The for for with in direct and and of on to the expression of the by The used mouse M. J. H. T. U. S. A. 2000; PubMed Scopus Google and and for with in and subsequently with The signal was a and of The was the and the was in the in a tissue and in for analysis and cells in of and was the cells the and in and in of and was the was by The was on of a by in a on the for to glyceraldehyde-3-phosphate and The used for are in of used for in a by cell and high A. Stein J.L. L. J.B. Stein G.S. Cell. Biol. 2001; PubMed Scopus Google Scholar). the Runx2 promoter the for and the TCF to The was with for the was in the of a of the a the for of and of a or was to the was with either or control for of the The on a and on H. P. M. Stein G.S. Stein J.L. Cell. Biol. PubMed Scopus Google with the was by of to a of for by with in was for The cell was with of of and or of The was by of the and the was by was and in of of was used for to the of with the and and and Runx2 by WNT in biological of Runx2 and WNT signaling was by the bone tissue of and of SFRP1 results in a significant increase in the and apoptosis in to bone density Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google Scholar). two of and was the bone of the We that Runx2 mRNA this in This induction in was by a increase in RUNX2 in This that osteoblast differentiation is a factor to the high bone mass phenotype the of Runx2 expression in WNT signaling and osteoblast we bone We that Runx2 mRNA to in The increase in TCF1 target of canonical WNT in the that the WNT pathway functions a in the The induction of Runx2 was by of RUNX2 target and a of in in gene expression and the of a mature in a J.B. A. C. M. Stein J.L. Stein G.S. Rev. Gene 2004; PubMed Google Scholar). gene which is to M. L. Stein J.L. J.B. Stein G.S. J. Cell. Biochem. PubMed Scopus Google Scholar), was in cells a the cell with osteoblast differentiation. We in expression of the the the of the in gene expression and of to expression evidence that the increase in Runx2 on a cell of mature in the in that to be the of Runx2 The increase in Runx2 expression and osteoblast in mouse bone is with our of osteoblast differentiation of bone cells Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google Scholar). our findings show that, in the absence of of WNT signaling, Runx2 expression is and promotes osteoblast differentiation. We that, in SFRP1 bone formation by in Runx2 gene WNT Runx2 regulation of Runx2 transcription by WNT signaling was addressed in a mouse the gene the control of the Runx2 The is in in development to formation of tissue C.J. H. Stein J.L. Stein G.S. J.B. Mech. Dev. 2002; PubMed Scopus Google Scholar). the pathway is linked to bone formation (15Boyden L.M. Mao J. Belsky J. Mitzner L. A. D. J. 2002; PubMed Scopus Google Scholar, J. 2002; PubMed Scopus Google Scholar, P. F. Bone 2004; PubMed Scopus Google Scholar, P. Zhao C. J. R.A. F. J. Bone PubMed Scopus Google Scholar, S. H. T. D. M. J. S. S. J. M. P. L.M. C. A. T. A. H. A. D. M. T. L. M. H. A. M.J. M. M. T. R. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. R. C. L. R.A. L. J. Cell Biol. 2002; PubMed Scopus Google Scholar, M. J. Bone 2004; PubMed Google Scholar, C. U. T. T. M. J. R. Development (Camb.). 2004; PubMed Scopus Google Scholar), we on regulation of the Runx2 gene by canonical WNT Runx2 promoter to WNT proteins was by activity in cells with Runx2 promoter activity was by in a of the cells of Runx2 promoter activity by of activity a increase in to canonical WNT signaling and of the osteoblast of We used the cell to Runx2 promoter activity in to in cells. We a induction of mouse promoter activity by the activity of the Runx2 promoter was with that of the resulted in the induction findings that WNT signaling Runx2 transcription in osteoprogenitor cells and embryonic mesenchymal cells to the induction of osteoblast the of the of the and promoter to and several that key regulatory are to the H. R. S. A. M. Jones S. J.B. Stein J.L. Stein G.S. J. Cell. 2000; PubMed Scopus Google Scholar, A. H. J. P. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), we on the promoter for of WNT family proteins with β-catenin to expression of target for the canonical WNT signaling pathway H. M. Genet. Full Text PDF PubMed Scopus Google Scholar), we the of TCF1 with a of WNT proteins on the Runx2 promoter in cells the absence of Runx2 promoter activity by However, the of TCF1 and either or Runx2 promoter activity to activity and with TCF1 resulted in a significant stimulation of Runx2 TCF1 activation of the Runx2 promoter by canonical WNT proteins in osteoprogenitor cells. We addressed the WNT/TCF1 activation of Runx2 is by the secreted for WNT SFRP1. We that SFRP1 the activity of the Runx2 promoter in the absence of WNT This that SFRP1 endogenous WNT signaling in cells C.J. A. M.J. Bone 2005; PubMed Scopus Google Scholar), which the Runx2 promoter Activation of the Runx2 promoter by and TCF1 was by SFRP1. We that SFRP1 activation of Runx2 by the canonical WNT proteins and for are Taken together, findings demonstrate that canonical signaling Runx2 promoter activity and that this regulation be by SFRP1. The Runx2 a TCF DNA-binding and a the Runx2 a TCF characterized by the is to We this element for the formation of a TCF1 DNA-binding complex. we used cells in which TCF1 was by analysis complex was with the Runx2 with the a mutation in the TCF This complex with the a on of to the formation of the a We RUNX2 in the a is in the results suggest that TCF1 with the element in the Runx2 promoter that is mouse and address the of the in regulation of the Runx2 the TCF element was revealed that mutation of the resulted in of activation by WNT and TCF1 results that the induction of the Runx2 promoter through the to We the promoter activity is gene expression the in cells. We cells with TCF1 and that endogenous Runx2 mRNA was by 7–8-fold by and TCF1 cells are with in Runx2 by either or TCF1 by significant in we in promoter However, the of endogenous Runx2 gene expression by and TCF1 was by the in of the TCF1 regulatory in the Runx2 gene promoter in cells of TCF1 and by of to the TCF element the Runx2 promoter The results show that TCF1 and β-catenin are with the The transcription in was in the Runx2 RUNX2 has been with the promoter of the Runx2 which several RUNX2 β-catenin/TCF1 and RUNX2 the promoter to control of The of the regulatory to the TCF and the of the Runx2 gene H. R. S. A. M. Jones S. J.B. Stein J.L. Stein G.S. J. Cell. 2000; PubMed Scopus Google to a interaction and effects on Runx2 We osteoprogenitor cells and and pluripotent mesenchymal cells. We that and TCF1 a increase in Runx2 promoter activity in cell RUNX2 of promoter was in the cell Coexpression of RUNX2 with the activation to the RUNX2 This that activation and RUNX2 two for regulation of Runx2 gene evidence of WNT and TCF1 activation of the Runx2 gene promoter has been by of the and recruitment of TCF1 to the Runx2 promoter in this in and in we that WNT signaling results in activation of the Runx2 promoter and endogenous Runx2 gene expression in pluripotent mesenchymal and osteoprogenitor cells. Our has a critical element in the promoter that WNT which is abrogated upon of this regulatory element to We have direct activation of Runx2 mediated by canonical WNT proteins with TCF1 in promoter and by in chromatin Our chromatin revealed of TCF1 with the Runx2 we that the WNT SFRP1 canonical WNT activation of the Runx2 promoter endogenous gene The in importance of bone formation mediated in through RUNX2 is by a activation of TCF1 and Runx2 in the Our of WNT activation of endogenous gene expression and Runx2 promoter activity in and osteoprogenitor cells that WNT signaling in mesenchymal cells be of Runx2 gene expression in the to and formation of a Our evidence for a by which the canonical WNT pathway promotes bone formation through activation of the osteogenic transcription factor which mesenchymal cells to the osteogenic This for in in mouse that the of bone formation, a of either or β-catenin signaling, with in Runx2 expression L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, T.P. D. C. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, U. S. A. 2005; PubMed Scopus Google Scholar). of β-catenin bone formation with in expression of L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, U. S. A. 2005; PubMed Scopus Google Scholar), of the β-catenin gene developmental causes and osteoblast differentiation L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, T.P. D. C. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). has been that a mesenchymal cell the osteoblast with induction of the bone-related transcription factors a increase in and of transcription factors and U. S. A. 2005; PubMed Scopus Google Scholar). induction of the Runx2 gene was in L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). We have a critical regulatory element in the Runx2 gene promoter that with the TCF1 transcription factor in osteogenic cells. Our of a increase in TCF1 mRNA upon WNT signaling in in the mouse the of TCF1 for induction of Runx2 gene expression and The mouse has a regulation of canonical WNT signaling through the TCF1 transcription factor that β-catenin activity in target The regulation of by signaling is J.E. T. T. M.J. Genet. 2001; PubMed Google Scholar, M. D. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. P. R. T. H. 1999; PubMed Scopus Google Scholar). activation of WNT signaling in of β-catenin that results in activation of J.E. T. T. M.J. Genet. 2001; PubMed Google Scholar, M. D. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). activation mutations in or β-catenin activates the transcription and of target is TCF1 in cells J. M. P. R. T. H. 1999; PubMed Scopus Google Scholar). Our that canonical WNT proteins increase the TCF1 and Runx2 in the hypothesis that RUNX2 is the by which WNT promotes of The expression of secreted WNT and has been for regulation of osteoblast differentiation C.J. A. M.J. Bone 2005; PubMed Scopus Google Scholar). Our of Runx2 and expression in bone of the SFRP1 mouse evidence for SFRP1 in osteoblast The of RUNX2 is to the osteogenic differentiation of and this is by osteocalcin. The in and in of a mature osteoblast phenotype the of growth of we in bone density or in of apoptosis and By of a high bone mass phenotype was and to apoptosis Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google Scholar). and of Runx2 was that the WNT signaling is a of bone formation in and However, a high bone mass phenotype be the of growth and bone the mouse, a of bone was the effects of WNT signaling mediated by Runx2 Zhao T. Stein G.S. J.B. 2004; PubMed Scopus Google Scholar). Our suggest that canonical WNT signaling contributes to bone formation by inhibition of formation by P. M. H. F. McMahon A.P. R.A. Dev. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), by of to osteoblast WNT signals are in structures that to development of skeletal (9Ikeya M. Takada S. Mech. Dev. 2001; 103: 27-33Crossref PubMed Scopus (124) Google Scholar, F. J.E. Development (Camb.). 2005; PubMed Scopus (274) Google Scholar, R. S. M. McMahon A.P. L. R. Development (Camb.). 2001; Google Scholar, Genet. PubMed Scopus Google Scholar, J. D. PubMed Scopus Google Scholar, R.A. Dev. PubMed Scopus Google Scholar, A. C. R. A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, H. M.J. F. Development (Camb.). 2005; PubMed Scopus Google Scholar). is that canonical WNT signaling the and differentiation of cells and T.P. D. C. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, P. M. H. F. McMahon A.P. R.A. Dev. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Runx2 is embryonic in the and in of that and bone (5Komori T. J. Cell. Biochem. 2005; 95: 445-453Crossref PubMed Scopus (274) Google Scholar, C.J. H. Stein J.L. Stein G.S. J.B. Mech. Dev. 2002; PubMed Scopus Google Scholar). Runx2 activation by WNT signaling in mesenchymal cells be required for differentiation the osteogenic The of the bone-related RUNX2 transcription factor a target gene of WNT/TCF1 in and pluripotent and osteoprogenitor cells a regulatory pathway that contributes to cell and to the for of mesenchymal cells the osteogenic for endochondral and bone formation. We propose that canonical WNT signaling contributes to bone formation through activation of the RUNX2 transcription which osteoblast differentiation. WNT regulation of Runx2 to be significant a pathway signaling, which Runx2 gene However, a direct regulatory element in the Runx2 promoter has been identified. is that target and Runx2 M.H. J. Biol. Full Text Full Text PDF PubMed Scopus Google and that F. J. Stein J.L. Stein G.S. J.B. A. J. Cell. 2005; PubMed Scopus Google Scholar, Stein J.L. Stein G.S. J.B. U. S. A. 2002; PubMed Scopus Google Scholar), in is evidence that a complex genetic interaction and growth factor-β receptor signaling for the development of the skeleton D. J. Dev. PubMed Scopus Google Scholar, S. Endocrinology. 2005; 146: PubMed Scopus Google Scholar, A. 2004; PubMed Scopus Google Scholar, S. J. J. Bone 2004; PubMed Scopus Google Scholar). how the and WNT pathways RUNX2 to osteoblast differentiation. Our findings the transcriptional in embryonic development that the formation of bone We for and and for