BACKGROUND: Runx2, formerly called PEBP2alphaA or Cbfa1, is a transcription factor whose deletion causes a complete lack of ossification. It directly regulates the expression of osteoblast-specific genes through the osteoblast-specific cis-acting element found in the promoter region of these genes. RESULTS: In this study, we have found conditions in which induction of the expression of Runx2 is not accompanied by expression of an osteoblast-specific gene, osteocalcin in C2C12 cells. This finding suggests the existence of a repressor of the activity of Runx2. We have then found that the homeobox protein Msx2 is able to repress the transcription activity of Runx2 by interacting with it. Furthermore, our results have shown that the other homeobox protein Dlx5 has an activity which interferes with both abilities of Msx2 to interact with Runx2 and repress its transcription activity. It has previously been shown that a missense mutation of Msx2 (P148H) causes Boston-type craniosynostosis in humans. Interestingly, while this mutant form of Msx2 was able to bind to Runx2 and repress its activity, these abilities of Msx2 (P148H) were not subject to regulation by Dlx5. CONCLUSION: These results suggest that regulation of the activity of Runx2 by Msx2 and Dlx5 plays an important role in the mammalian skull development.

This article has been cited by other articles:

				A. Jager, D. Kunert, T. Friesen, D. Zhang, S. Lossdorfer, and W. Gotz Cellular and extracellular factors in early root resorption repair in the rat Eur J Orthod, August 1, 2008; 30(4): 336 - 345. [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]

				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]

				A. B. Hjelmeland, S. H. Schilling, X. Guo, D. Quarles, and X.-F. Wang Loss of Smad3-Mediated Negative Regulation of Runx2 Activity Leads to an Alteration in Cell Fate Determination Mol. Cell. Biol., November 1, 2005; 25(21): 9460 - 9468. [Abstract] [Full Text] [PDF]

				M.-H. Lee, Y.-J. Kim, W.-J. Yoon, J.-I. Kim, B.-G. Kim, Y.-S. Hwang, J. M. Wozney, X.-Z. Chi, S.-C. Bae, K.-Y. Choi, et al. Dlx5 Specifically Regulates Runx2 Type II Expression by Binding to Homeodomain-response Elements in the Runx2 Distal Promoter J. Biol. Chem., October 21, 2005; 280(42): 35579 - 35587. [Abstract] [Full Text] [PDF]

				H. Roca, M. Phimphilai, R. Gopalakrishnan, G. Xiao, and R. T. Franceschi Cooperative Interactions between RUNX2 and Homeodomain Protein-binding Sites Are Critical for the Osteoblast-specific Expression of the Bone Sialoprotein Gene J. Biol. Chem., September 2, 2005; 280(35): 30845 - 30855. [Abstract] [Full Text] [PDF]

				Y.-J. Kim, M.-H. Lee, J. M. Wozney, J.-Y. Cho, and H.-M. Ryoo Bone Morphogenetic Protein-2-induced Alkaline Phosphatase Expression Is Stimulated by Dlx5 and Repressed by Msx2 J. Biol. Chem., December 3, 2004; 279(49): 50773 - 50780. [Abstract] [Full Text] [PDF]

				M. Q. Hassan, A. Javed, M. I. Morasso, J. Karlin, M. Montecino, A. J. van Wijnen, G. S. Stein, J. L. Stein, and J. B. Lian Dlx3 Transcriptional Regulation of Osteoblast Differentiation: Temporal Recruitment of Msx2, Dlx3, and Dlx5 Homeodomain Proteins to Chromatin of the Osteocalcin Gene Mol. Cell. Biol., October 15, 2004; 24(20): 9248 - 9261. [Abstract] [Full Text] [PDF]

				F. Ichida, R. Nishimura, K. Hata, T. Matsubara, F. Ikeda, K. Hisada, H. Yatani, X. Cao, T. Komori, A. Yamaguchi, et al. Reciprocal Roles of Msx2 in Regulation of Osteoblast and Adipocyte Differentiation J. Biol. Chem., August 6, 2004; 279(32): 34015 - 34022. [Abstract] [Full Text] [PDF]

				O. L. Sierra, S.-L. Cheng, A. P. Loewy, N. Charlton-Kachigian, and D. A. Towler MINT, the Msx2 Interacting Nuclear Matrix Target, Enhances Runx2-dependent Activation of the Osteocalcin Fibroblast Growth Factor Response Element J. Biol. Chem., July 30, 2004; 279(31): 32913 - 32923. [Abstract] [Full Text] [PDF]

				S. Brunelli, E. Tagliafico, F. G. De Angelis, R. Tonlorenzi, S. Baesso, S. Ferrari, M. Niinobe, K. Yoshikawa, R. J. Schwartz, I. Bozzoni, et al. Msx2 and Necdin Combined Activities Are Required for Smooth Muscle Differentiation in Mesoangioblast Stem Cells Circ. Res., June 25, 2004; 94(12): 1571 - 1578. [Abstract] [Full Text] [PDF]

				T. Yoshizawa, F. Takizawa, F. Iizawa, O. Ishibashi, H. Kawashima, A. Matsuda, N. Endo, and H. Kawashima Homeobox Protein Msx2 Acts as a Molecular Defense Mechanism for Preventing Ossification in Ligament Fibroblasts Mol. Cell. Biol., April 15, 2004; 24(8): 3460 - 3472. [Abstract] [Full Text] [PDF]

				M. Han, X. Yang, J. E. Farrington, and K. Muneoka Digit regeneration is regulated by Msx1 and BMP4 in fetal mice Development, November 1, 2003; 130(21): 5123 - 5132. [Abstract] [Full Text] [PDF]

				M.-H. Lee, Y.-J. Kim, H.-J. Kim, H.-D. Park, A.-R. Kang, H.-M. Kyung, J.-H. Sung, J. M. Wozney, H.-J. Kim, and H.-M. Ryoo BMP-2-induced Runx2 Expression Is Mediated by Dlx5, and TGF-{beta}1 Opposes the BMP-2-induced Osteoblast Differentiation by Suppression of Dlx5 Expression J. Biol. Chem., September 5, 2003; 278(36): 34387 - 34394. [Abstract] [Full Text] [PDF]

				C. B. Kimmel, B. Ullmann, M. Walker, C. T. Miller, and J. G. Crump Endothelin 1-mediated regulation of pharyngeal bone development in zebrafish Development, April 1, 2003; 130(7): 1339 - 1351. [Abstract] [Full Text] [PDF]

				K. L. Tyson, J. L. Reynolds, R. McNair, Q. Zhang, P. L. Weissberg, and C. M. Shanahan Osteo/Chondrocytic Transcription Factors and Their Target Genes Exhibit Distinct Patterns of Expression in Human Arterial Calcification Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 489 - 494. [Abstract] [Full Text] [PDF]

				B. Lecka-Czernik, E. J. Moerman, D. F. Grant, J. M. Lehmann, S. C. Manolagas, and R. L. Jilka Divergent Effects of Selective Peroxisome Proliferator-Activated Receptor-{gamma}2 Ligands on Adipocyte Versus Osteoblast Differentiation Endocrinology, June 1, 2002; 143(6): 2376 - 2384. [Abstract] [Full Text] [PDF]

				R. F. Robledo, L. Rajan, X. Li, and T. Lufkin The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development Genes & Dev., May 1, 2002; 16(9): 1089 - 1101. [Abstract] [Full Text] [PDF]

				L. L. Demer Adipose Rex: Fat and Fats That Rule Differentiation Circ. Res., February 22, 2002; 90(3): 241 - 243. [Full Text] [PDF]