title: Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells.
abstract: 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.
authors.affiliation: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, Saitama 350-1241, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, Saitama 350-1241, Japan.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Horie-Inoue
authors.affiliation: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, Saitama 350-1241, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300.
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
authors.affiliation: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, Saitama 350-1241, Japan; Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. Electronic address: s_inoue@saitama-med.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism / Q000502:physiology*; D012293:Rifampin / Q000494:pharmacology; D014158:Transcription, Genetic; D024482:Vitamin K 2 / Q000378:metabolism*
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D024482:Vitamin K 2; D003094:Collagen; D012293:Rifampin