HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 39, 33132-33140, September 30, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/39/33132    most recent M500608200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gaur, T. Articles by Lian, J. B. Search for Related Content PubMed PubMed Citation Articles by Gaur, T. Articles by Lian, J. B. Social Bookmarking                      What's this?

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, and Jane B. Lian1

From the Department of Cell Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106 and the Women's Health Research Institute, Wyeth Research, Collegeville, Pennsylvania 19426

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

Received for publication, January 18, 2005 , and in revised form, June 3, 2005.

^* This work was supported by National Institutes of Health Grants AR39588, P01 AR48818, and P30 DK32520. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell Biology and the Cancer Center, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655-0106. Tel.: 508-856-5625; Fax: 508-856-6800; E-mail: jane.lian{at}umassmed.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Z. Li, M. Q. Hassan, M. Jafferji, R. I. Aqeilan, R. Garzon, C. M. Croce, A. J. van Wijnen, J. L. Stein, G. S. Stein, and J. B. Lian Biological Functions of miR-29b Contribute to Positive Regulation of Osteoblast Differentiation J. Biol. Chem., June 5, 2009; 284(23): 15676 - 15684. [Abstract] [Full Text] [PDF]

				M. J. Nemeth, K. K. Mak, Y. Yang, and D. M. Bodine {beta}-Catenin Expression in the Bone Marrow Microenvironment Is Required for Long-Term Maintenance of Primitive Hematopoietic Cells Stem Cells, May 1, 2009; 27(5): 1109 - 1119. [Abstract] [Full Text] [PDF]

				G. Liu, S. Vijayakumar, L. Grumolato, R. Arroyave, H. Qiao, G. Akiri, and S. A. Aaronson Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells J. Cell Biol., April 6, 2009; 185(1): 67 - 75. [Abstract] [Full Text] [PDF]

				H. Miraoui, K. Oudina, H. Petite, Y. Tanimoto, K. Moriyama, and P. J. Marie Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling J. Biol. Chem., February 20, 2009; 284(8): 4897 - 4904. [Abstract] [Full Text] [PDF]

				Y. Zhang, M. Q. Hassan, R.-L. Xie, J. R. Hawse, T. C. Spelsberg, M. Montecino, J. L. Stein, J. B. Lian, A. J. van Wijnen, and G. S. Stein Co-stimulation of the Bone-related Runx2 P1 Promoter in Mesenchymal Cells by SP1 and ETS Transcription Factors at Polymorphic Purine-rich DNA Sequences (Y-repeats) J. Biol. Chem., January 30, 2009; 284(5): 3125 - 3135. [Abstract] [Full Text] [PDF]

				L. Xiao, P. Liu, X. Li, T. Doetschman, J. D. Coffin, H. Drissi, and M. M. Hurley Exported 18-kDa Isoform of Fibroblast Growth Factor-2 Is a Critical Determinant of Bone Mass in Mice J. Biol. Chem., January 30, 2009; 284(5): 3170 - 3182. [Abstract] [Full Text] [PDF]

				J. J. Pinzone, B. M. Hall, N. K. Thudi, M. Vonau, Y.-W. Qiang, T. J. Rosol, and J. D. Shaughnessy Jr The role of Dickkopf-1 in bone development, homeostasis, and disease Blood, January 15, 2009; 113(3): 517 - 525. [Abstract] [Full Text] [PDF]

				S. Suzuki, S. Sembon, M. Iwamoto, D. Fuchimoto, and A. Onishi Identification of genes downregulated during differentiation of porcine mesenteric adipocytes J Anim Sci, December 1, 2008; 86(12): 3367 - 3376. [Abstract] [Full Text] [PDF]

				M. P. Alfaro, M. Pagni, A. Vincent, J. Atkinson, M. F. Hill, J. Cates, J. M. Davidson, J. Rottman, E. Lee, and P. P. Young The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair PNAS, November 25, 2008; 105(47): 18366 - 18371. [Abstract] [Full Text] [PDF]

				Z. Hamidouche, E. Hay, P. Vaudin, P. Charbord, R. Schule, P. J. Marie, and O. Fromigue FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/{beta}-catenin signaling-dependent Runx2 expression FASEB J, November 1, 2008; 22(11): 3813 - 3822. [Abstract] [Full Text] [PDF]

				N. Case, M. Ma, B. Sen, Z. Xie, T. S. Gross, and J. Rubin {beta}-Catenin Levels Influence Rapid Mechanical Responses in Osteoblasts J. Biol. Chem., October 24, 2008; 283(43): 29196 - 29205. [Abstract] [Full Text] [PDF]

				Z. Li, M. Q. Hassan, S. Volinia, A. J. van Wijnen, J. L. Stein, C. M. Croce, J. B. Lian, and G. S. Stein A microRNA signature for a BMP2-induced osteoblast lineage commitment program PNAS, September 16, 2008; 105(37): 13906 - 13911. [Abstract] [Full Text] [PDF]

				D. Ambrosetti, G. Holmes, A. Mansukhani, and C. Basilico Fibroblast Growth Factor Signaling Uses Multiple Mechanisms To Inhibit Wnt-Induced Transcription in Osteoblasts Mol. Cell. Biol., August 1, 2008; 28(15): 4759 - 4771. [Abstract] [Full Text] [PDF]

				S.-L. Cheng, J.-S. Shao, J. Cai, O. L. Sierra, and D. A. Towler Msx2 Exerts Bone Anabolism via Canonical Wnt Signaling J. Biol. Chem., July 18, 2008; 283(29): 20505 - 20522. [Abstract] [Full Text] [PDF]

				E.L. Scheller, J. Chang, and C.Y. Wang Wnt/{beta}-catenin Inhibits Dental Pulp Stem Cell Differentiation Journal of Dental Research, February 1, 2008; 87(2): 126 - 130. [Abstract] [Full Text] [PDF]

				H. Zhou, W. Mak, Y. Zheng, C. R. Dunstan, and M. J. Seibel Osteoblasts Directly Control Lineage Commitment of Mesenchymal Progenitor Cells through Wnt Signaling J. Biol. Chem., January 25, 2008; 283(4): 1936 - 1945. [Abstract] [Full Text] [PDF]

				L. S. H. Nissen-Meyer, R. Jemtland, V. T. Gautvik, M. E. Pedersen, R. Paro, D. Fortunati, D. D. Pierroz, V. A. Stadelmann, S. Reppe, F. P. Reinholt, et al. Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice J. Cell Sci., August 15, 2007; 120(16): 2785 - 2795. [Abstract] [Full Text] [PDF]

				X.-H. Liu, A. Kirschenbaum, S. Yao, G. Liu, S. A. Aaronson, and A. C. Levine Androgen-Induced Wnt Signaling in Preosteoblasts Promotes the Growth of MDA-PCa-2b Human Prostate Cancer Cells Cancer Res., June 15, 2007; 67(12): 5747 - 5753. [Abstract] [Full Text] [PDF]

				D. A. Glass II and G. Karsenty In Vivo Analysis of Wnt Signaling in Bone Endocrinology, June 1, 2007; 148(6): 2630 - 2634. [Abstract] [Full Text] [PDF]

				S. Kang, C. N. Bennett, I. Gerin, L. A. Rapp, K. D. Hankenson, and O. A. MacDougald Wnt Signaling Stimulates Osteoblastogenesis of Mesenchymal Precursors by Suppressing CCAAT/Enhancer-binding Protein {alpha} and Peroxisome Proliferator-activated Receptor {gamma} J. Biol. Chem., May 11, 2007; 282(19): 14515 - 14524. [Abstract] [Full Text] [PDF]

				M. Q. Hassan, R. Tare, S. H. Lee, M. Mandeville, B. Weiner, M. Montecino, A. J. van Wijnen, J. L. Stein, G. S. Stein, and J. B. Lian HOXA10 Controls Osteoblastogenesis by Directly Activating Bone Regulatory and Phenotypic Genes Mol. Cell. Biol., May 1, 2007; 27(9): 3337 - 3352. [Abstract] [Full Text] [PDF]

				P. V. Bodine Wnt Signaling in Bone IBMS BoneKEy, March 1, 2007; 4(3): 108 - 123. [Abstract] [Full Text] [PDF]

				M. I. Reinhold and M. C. Naski Direct Interactions of Runx2 and Canonical Wnt Signaling Induce FGF18 J. Biol. Chem., February 9, 2007; 282(6): 3653 - 3663. [Abstract] [Full Text] [PDF]

				M. Q. Hassan, R. S. Tare, S. H. Lee, M. Mandeville, M. I. Morasso, A. Javed, A. J. van Wijnen, J. L. Stein, G. S. Stein, and J. B. Lian BMP2 Commitment to the Osteogenic Lineage Involves Activation of Runx2 by DLX3 and a Homeodomain Transcriptional Network J. Biol. Chem., December 29, 2006; 281(52): 40515 - 40526. [Abstract] [Full Text] [PDF]

				N. Giuliani, V. Rizzoli, and G. D. Roodman Multiple myeloma bone disease: pathophysiology of osteoblast inhibition Blood, December 15, 2006; 108(13): 3992 - 3996. [Abstract] [Full Text] [PDF]

				V. Plaisance, A. Abderrahmani, V. Perret-Menoud, P. Jacquemin, F. Lemaigre, and R. Regazzi MicroRNA-9 Controls the Expression of Granuphilin/Slp4 and the Secretory Response of Insulin-producing Cells J. Biol. Chem., September 15, 2006; 281(37): 26932 - 26942. [Abstract] [Full Text] [PDF]

				S. J. Rodda and A. P. McMahon Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors Development, August 15, 2006; 133(16): 3231 - 3244. [Abstract] [Full Text] [PDF]

				D. Spater, T. P. Hill, R. J. O'Sullivan, M. Gruber, D. A. Conner, and C. Hartmann Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis Development, August 1, 2006; 133(15): 3039 - 3049. [Abstract] [Full Text] [PDF]

				I. Hernandez-Gonzalez, I. Gonzalez-Robayna, M. Shimada, C. M. Wayne, S. A. Ochsner, L. White, and J. S. Richards Gene Expression Profiles of Cumulus Cell Oocyte Complexes during Ovulation Reveal Cumulus Cells Express Neuronal and Immune-Related Genes: Does this Expand Their Role in the Ovulation Process? Mol. Endocrinol., June 1, 2006; 20(6): 1300 - 1321. [Abstract] [Full Text] [PDF]

				L. L. Demer and Y. Tintut Pitting Phosphate Transport Inhibitors Against Vascular Calcification Circ. Res., April 14, 2006; 98(7): 857 - 859. [Full Text] [PDF]