Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice.
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.
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan; The First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
Kazuaki
K
Miyagawa
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
Miwa
M
Yamazaki
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
Masanobu
M
Kawai
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan; The First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
Jin
J
Nishino
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
Takao
T
Koshimizu
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yasuhisa
Y
Ohata
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
Kanako
K
Tachikawa
Department of Molecular and Cellular Biology of Mineralized Tissues, Kanagawa Dental College, Yokosuka, Kanagawa, Japan.
Yuko
Y
Mikuni-Takagaki
The First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
Mikihiko
M
Kogo
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Keiichi
K
Ozono
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
Toshimi
T
Michigami
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D007015:Hypophosphatemia, Familial / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D010011:Osteocytes / Q000378:metabolism*; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C509696:FAM20C protein, mouse; C000717428:Fgf23 protein, mouse; C493587:Slc20a1 protein, mouse; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23