Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice

• Published in: PloS one Vol. 9; no. 4; p. e93840
• Main Authors: Miyagawa, Kazuaki, Yamazaki, Miwa, Kawai, Masanobu, Nishino, Jin, Koshimizu, Takao, Ohata, Yasuhisa, Tachikawa, Kanako, Mikuni-Takagaki, Yuko, Kogo, Mikihiko, Ozono, Keiichi, Michigami, Toshimi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2014; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Biocompatibility; Biology and Life Sciences; Bone and Bones - metabolism; Bones; Calcitriol; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Childrens health; Dentistry; Dihydroxyvitamin D3; Disease Models, Animal; EGR-1 protein; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fetuses; Fibroblast growth factor 1; Fibroblast growth factor 2; Fibroblast growth factor 23; Fibroblast growth factor receptors; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene regulation; Genes; Genotypes; Growth factors; Homeostasis; Hypophosphatemia; Hypophosphatemia, Familial - genetics; Hypophosphatemia, Familial - metabolism; Kinases; Ligands; Low density lipoprotein receptors; Maternal & child health; Maxillofacial surgery; Medicine and Health Sciences; Metabolism; Mice; Mineral metabolism; Mineralization; Mutation; Osteoblasts; Osteoblasts - metabolism; Osteocytes; Osteocytes - metabolism; Pathogenesis; Pediatrics; Phosphates; Physiological aspects; Pit1 protein; Proteins; Receptors; Research and Analysis Methods; Rodents; Signaling; Sodium; Sodium-Phosphate Cotransporter Proteins, Type III - genetics; Sodium-Phosphate Cotransporter Proteins, Type III - metabolism; Surgery; University graduates; Up-Regulation; Vitamin D; Vitamin D3; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0093840

Osteocytes express multiple genes involved in mineral metabolism including PHEX, FGF23, DMP1 and FAM20C. In Hyp mice, a murine model for X-linked hypophosphatemia (XLH), Phex deficiency results in the overproduction of FGF23 in osteocytes, which leads to hypophosphatemia and impaired vitamin D metabolism. In this study, to further clarify the abnormality in osteocytes of Hyp mice, we obtained detailed gene expression profiles in osteoblasts and osteocytes isolated from the long bones of 20-week-old Hyp mice and wild-type (WT) control mice. The expression of Fgf23, Dmp1, and Fam20c was higher in osteocytic cells than in osteoblastic cells in both genotypes, and was up-regulated in Hyp cells. Interestingly, the up-regulation of these genes in Hyp bones began before birth. On the other hand, the expression of Slc20a1 encoding the sodium/phosphate (Na+/Pi) co-transporter Pit1 was increased in osteoblasts and osteocytes from adult Hyp mice, but not in Hyp fetal bones. The direct effects of extracellular Pi and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on isolated osteoblastic and osteocytic cells were also investigated. Twenty-four-hour treatment with 10-8 M 1,25(OH)2D3 increased the expression of Fgf23 in WT osteoblastic cells but not in osteocytic cells. Dmp1 expression in osteocytic cells was increased due to the 24-hour treatment with 10 mM Pi and was suppressed by 10-8 M 1,25(OH)2D3 in WT osteocytic cells. We also found the up-regulation of the genes for FGF1, FGF2, their receptors, and Egr-1 which is a target of FGF signaling, in Hyp osteocytic cells, suggesting the activation of FGF/FGFR signaling. These results implicate the complex gene dysregulation in osteoblasts and osteocytes of Hyp mice, which might contribute to the pathogenesis.