title: Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells.
abstract: 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 gamma-glutamyl carboxylase (GGCX), we have previously shown that vitamin K(2) 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 K(2) 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 K(2) isoform MK-7, vitamin K(1), 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 K(2) 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.
authors.affiliation: Division of Gene Regulation and Signal Transduction,, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ichikawa
authors.forename: K
authors.initials: K
authors.lastname: Horie-Inoue
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: B
authors.initials: B
authors.lastname: Blumberg
authors.forename: S
authors.initials: S
authors.lastname: Inoue
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D055436:Growth Differentiation Factor 15; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D019485:Bone Morphogenetic Proteins; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D006023:Glycoproteins; D055436:Growth Differentiation Factor 15; D036341:Intercellular Signaling Peptides and Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C114997:STC2 protein, human; D024482:Vitamin K 2; C030814:menatetrenone; D017868:Cyclic AMP-Dependent Protein Kinases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase