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Molecular and Cellular Biology, November 2007, p. 7947-7954, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.00813-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Vitamin K Induces Osteoblast Differentiation through Pregnane X Receptor-Mediated Transcriptional Control of the Msx2 Gene{triangledown}

Mamoru Igarashi,1 Yoshiko Yogiashi,1,2 Masatomo Mihara,1 Ichiro Takada,1 Hirochika Kitagawa,1 and Shigeaki Kato1,2*

The Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan,1 ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan2

Received 9 May 2007/ Returned for modification 11 June 2007/ Accepted 31 August 2007

Vitamin K is a fat-soluble vitamin that serves as a coenzyme for vitamin K-dependent carboxylase. Besides its canonical action, vitamin K binds to the steroid and xenobiotic receptor (SXR)/pregnane X receptor (PXR) and modulates gene transcription. To determine if the osteoprotective action of vitamin K is the result of the PXR/SXR pathway, we screened by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis the PXR/SXR target genes in an osteoblastic cell line (MC3T3-E1) treated with a vitamin K2 (menaquinone 4 [MK4]). Osteoblastic differentiation of MC3T3-E1 cells was induced by MK4. Msx2, an osteoblastogenic transcription factor, was identified as an MK4-induced gene. Functional analysis of the Msx2 gene promoter mapped a vitamin K-responsive element (PXR-responsive element [PXRE]) that was directly bound by a PXR/retinoid X receptor {alpha} heterodimer. In a chromatin immunoprecipitation analysis, PXR was recruited together with a coactivator, p300, to the PXRE in the Msx2 promoter. MK4-bound PXR cooperated with estrogen-bound estrogen receptor {alpha} to control transcription at the Msx2 promoter. Knockdown of either PXR or Msx2 attenuated the effect of MK4 on osteoblastic differentiation. Thus, the present study suggests that Msx2 is a target gene for PXR activated by vitamin K and suggests that the osteoprotective action of MK4 in the human mediates, at least in part, a genomic pathway of vitamin K signaling.

* Corresponding author. Mailing address: The Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Phone: 81-3-5841-8478. Fax: 81-3-5841-8477. E-mail: uskato{at}mail.ecc.u-tokyo.ac.jp

{triangledown} Published ahead of print on 17 September 2007.

Molecular and Cellular Biology, November 2007, p. 7947-7954, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.00813-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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