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Molecular and Cellular Biology, February 2008, p. 1147-1160, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01771-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Runx2 Represses Myocardin-Mediated Differentiation and Facilitates Osteogenic Conversion of Vascular Smooth Muscle Cells{triangledown}

Toru Tanaka,1 Hiroko Sato,1 Hiroshi Doi,1 Carolina A. Yoshida,3 Takehisa Shimizu,1 Hiroki Matsui,1 Miki Yamazaki,1 Hideo Akiyama,2 Keiko Kawai-Kowase,1 Tatsuya Iso,1 Toshihisa Komori,3 Masashi Arai,1 and Masahiko Kurabayashi1*

Departments of Medicine and Biological Science,1 Ophthalmology, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371-8511, Japan,2 Department of Cell Biology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan3

Received 27 September 2007/ Accepted 5 November 2007

Phenotypic plasticity and the switching of vascular smooth muscle cells (SMCs) play a critical role in atherosclerosis. Although Runx2, a key osteogenic transcription factor, is expressed in atherosclerotic plaques, the molecular mechanisms by which Runx2 regulates SMC differentiation remain unclear. Here we demonstrated that Runx2 repressed SMC differentiation induced by myocardin, which acts as a coactivator for serum response factor (SRF). Myocardin-mediated induction of SMC gene expression was enhanced in mouse embryonic fibroblasts derived from Runx2 null mice compared to wild-type mice. Forced expression of Runx2 decreased the expression of SMC genes and promoted osteogenic gene expression, whereas the reduction of Runx2 expression by small interfering RNA enhanced SMC differentiation in human aortic SMCs. Runx2 interacted with SRF and interfered with the formation of the SRF/myocardin ternary complex. Thus, this study provides the first evidence that Runx2 inhibits SRF-dependent transcription, as a corepressor independent of its DNA binding. We propose that Runx2 plays a pivotal role in osteogenic conversion tightly coupled with repression of the SMC phenotype in atherosclerotic lesions.

* Corresponding author. Mailing address: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371-8511, Japan. Phone: 81-27-220-8140. Fax: 81-27-220-8150. E-mail: mkuraba{at}med.gunma-u.ac.jp

{triangledown} Published ahead of print on 26 November 2007.

Molecular and Cellular Biology, February 2008, p. 1147-1160, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01771-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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