title: Extracellular Phosphate Induces the Expression of Dentin Matrix Protein 1 Through the FGF Receptor in Osteoblasts.
abstract: Dentin matrix protein 1 (Dmp1) is an extracellular matrix protein involved in phosphate metabolism and biomineralization, and its expression markedly increases during the maturation of osteoblasts into osteocytes. We previously reported that an increased level of inorganic phosphate (Pi) in media up-regulated the expression of Dmp1 in primary osteocytes isolated from mouse bones. In the present study, we found that elevated extracellular Pi strongly induced the expression of Dmp1 in osteoblasts and explored its underlying mechanism of action. In an osteoblastic cell line MC3T3-E1, increases in extracellular Pi induced the phosphorylation of ERK1/2 and up-regulated the expression of Dmp1, fibroblast growth factor 2 (Fgf2), and Fgf receptor 1 (Fgfr1). A co-treatment with the MEK inhibitor U0126 abolished the increase in the expression of Dmp1 and Fgfr1 by elevated Pi, suggesting the involvement of the MEK/ERK pathway in this up-regulation. Elevated extracellular Pi also resulted in the phosphorylation of FGF receptor substrate 2α (FRS2α), which was diminished by knockdown of Slc20a1 encoding Pit1 sodium-phosphate co-transporter. The co-treatment with an inhibitor against FGFR (SU5402) abolished the up-regulation of Dmp1 induced by elevated extracellular Pi. In primary osteoblasts, a treatment with 4 mM Pi transiently increased the expression of early growth response 1 (Egr1) before the up-regulation of Dmp1. These results indicate that FGFR mediates the direct effects of extracellular Pi on the expression of Dmp1 in osteoblasts and enhance the close relationship between the signaling evoked by elevated extracellular Pi and FGF/FGFR signaling. J. Cell. Biochem. 118: 1151-1163, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.|First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Nishino
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawai
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Tachikawa
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.|Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.|First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Miyagawa
authors.affiliation: First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Kogo
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
mesh_terms: D016475:3T3 Cells; D000818:Animals; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010710:Phosphates / Q000494:pharmacology*; D010766:Phosphorylation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D010710:Phosphates; D016222:Fibroblast Growth Factor 2; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: DENTIN MATRIX PROTEIN 1; EXTRACELLULAR PHOSPHATE; FIBROBLAST GROWTH FACTOR RECEPTOR; OSTEOBLAST; SIGNALING