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Molecular and Cellular Biology, August 2004, p. 6560-6568, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6560-6568.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Bone Morphogenetic Protein 2-Induced Osteoblast Differentiation Requires Smad-Mediated Down-Regulation of Cdk6

Toru Ogasawara,1,2 Hiroshi Kawaguchi,2 Shigeki Jinno,1 Kazuto Hoshi,2 Keiji Itaka,2 Tsuyoshi Takato,2 Kozo Nakamura,2 and Hiroto Okayama1*

Departments of Biochemistry and Molecular Biology,1 Sensory and Motor System Medicine, The University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan2

Received 31 March 2004/ Accepted 8 May 2004

Because a temporal arrest in the G1 phase of the cell cycle is thought to be a prerequisite for cell differentiation, we investigated cell cycle factors that critically influence the differentiation of mouse osteoblastic MC3T3-E1 cells induced by bone morphogenetic protein 2 (BMP-2), a potent inducer of osteoblast differentiation. Of the G1 cell cycle factors examined, the expression of cyclin-dependent kinase 6 (Cdk6) was found to be strongly down-regulated by BMP-2/Smads signaling, mainly via transcriptional repression. The enforced expression of Cdk6 blocked BMP-2-induced osteoblast differentiation to various degrees, depending on the level of its overexpression. However, neither BMP-2 treatment nor Cdk6 overexpression significantly affected cell proliferation, suggesting that the inhibitory effect of Cdk6 on cell differentiation was exerted by a mechanism that is largely independent of its cell cycle regulation. These results indicate that Cdk6 is a critical regulator of BMP-2-induced osteoblast differentiation and that its Smads-mediated down-regulation is essential for efficient osteoblast differentiation.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan. Phone: 81-3-5841-3440. Fax: 81-3-3815-1490. E-mail: okayama-tky{at}umin.ac.jp.

Molecular and Cellular Biology, August 2004, p. 6560-6568, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6560-6568.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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