HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ichikawa, T Articles by Inoue, S Search for Related Content PubMed PubMed Citation Articles by Ichikawa, T Articles by Inoue, S

¹ Division of Gene Regulation and Signal Transduction,, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama 350-1241, Japan ² Department of Developmental and Cell Biology,, University of California, Irvine, California 92697-2300, USA ³ Department of Geriatric Medicine,, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

(Correspondence should be addressed to S Inoue; Email: inoue-ger{at}h.u-tokyo.ac.jp)

The authors have nothing to declare.

Vitamin K is known as a critical nutrient required for bone homeostasis and blood coagulation, and it is clinically used as a therapeutic agent for osteoporosis in Japan. Besides its enzymatic action as a cofactor of vitamin K-dependent -glutamyl carboxylase (GGCX), we have previously shown that vitamin K₂ is a transcriptional regulator of bone marker genes and extracellular matrix-related genes, by activating the steroid and xenobiotic receptor (SXR). To explore a novel action of vitamin K in osteoblastic cells, we identified genes up-regulated by a vitamin K₂ isoform menaquinone-4 (MK-4) using oligonucleotide microarray analysis. Among these up-regulated genes by MK-4, growth differentiation factor 15 (GDF15) and stanniocalcin 2 (STC2) were identified as novel MK-4 target genes independent of GGCX and SXR pathways in human and mouse osteoblastic cells. The induction of GDF15 and STC2 is likely specific to MK-4, as it was not exerted by another vitamin K₂ isoform MK-7, vitamin K₁, or the MK-4 side chain structure geranylgeraniol. Investigation of the involved signaling pathways revealed that MK-4 enhanced the phosphorylation of protein kinase A (PKA), and the MK-4-dependent induction of both GDF15 and STC2 genes was reduced by the treatment with a PKA inhibitor H89 or siRNA against PKA. These results suggest that vitamin K₂ modulates its target gene expression in osteoblastic cells through the PKA-dependent mechanism, which may be distinct from the previously known vitamin K signaling pathways.

This article has been cited by other articles:

				G. J. Atkins, K. J. Welldon, A. R. Wijenayaka, L. F. Bonewald, and D. M. Findlay Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by {gamma}-carboxylation-dependent and -independent mechanisms Am J Physiol Cell Physiol, December 1, 2009; 297(6): C1358 - C1367. [Abstract] [Full Text] [PDF]

				A. Rubinacci Expanding the functional spectrum of vitamin K in bone. Focus on: "Vitamin K promotes mineralization, osteoblast to osteocyte transition, and an anti-catabolic phenotype by {gamma}-carboxylation-dependent and -independent mechanisms" Am J Physiol Cell Physiol, December 1, 2009; 297(6): C1336 - C1338. [Full Text] [PDF]