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J. Biol. Chem., Vol. 281, Issue 25, 16927-16934, June 23, 2006

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Steroid and Xenobiotic Receptor SXR Mediates Vitamin K₂-activated Transcription of Extracellular Matrix-related Genes and Collagen Accumulation in Osteoblastic Cells^*

Tomoe Ichikawa, Kuniko Horie-Inoue, Kazuhiro Ikeda, Bruce Blumberg, and Satoshi Inoue^¶1

From the Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, Saitama 350-1241, Japan, the Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, and the ^¶Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan

Vitamin K₂ is a critical nutrient required for blood coagulation. It also plays a key role in bone homeostasis and is a clinically effective therapeutic agent for osteoporosis. We previously demonstrated that vitamin K₂ is a transcriptional regulator of bone marker genes in osteoblastic cells and that it may potentiate bone formation by activating the steroid and xenobiotic receptor, SXR. To explore the SXR-mediated vitamin K₂ signaling network in bone homeostasis, we identified genes up-regulated by both vitamin K₂ and the prototypical SXR ligand, rifampicin, in osteoblastic cells using oligonucleotide microarray analysis and quantitative reverse transcription-PCR. Fourteen genes were up-regulated by both ligands. Among these, tsukushi, matrilin-2, and CD14 antigen were shown to be primary SXR target genes. Moreover, collagen accumulation in osteoblastic MG63 cells was enhanced by vitamin K₂ treatment. Gain- and loss-of-function analyses showed that the small leucine-rich proteoglycan, tsukushi, contributes to vitamin K₂-mediated enhancement of collagen accumulation. Our results suggest a new function for vitamin K₂ in bone formation as a transcriptional regulator of extracellular matrix-related genes, that are involved in the collagen assembly.

Received for publication, January 30, 2006 , and in revised form, March 28, 2006.

^* This work was supported in part by grants-in-aid from the Ministry of Health, Labor and Welfare and from the Japan Society for the Promotion of Science and by a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan and for Development of New Technology from The Promotion and Mutual Aid Corporation for Private Schools of Japan. This work was also supported by National Institutes of Health Grant GM-060572 (to B. B.). 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.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan. Tel.: 81-42-985-7206; Fax: 81-42-985-7209; E-mail: s_inoue{at}saitama-med.ac.jp.

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