Dysregulated Gene Expression in the Primary Osteoblasts and Osteocytes Isolated from Hypophosphatemic <i>Hyp</i> Mice

<div><p>Osteocytes express multiple genes involved in mineral metabolism including PHEX, FGF23, DMP1 and FAM20C. In <i>Hyp</i> 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 <i>Hyp</i> mice, we obtained detailed gene expression profiles in osteoblasts and osteocytes isolated from the long bones of 20-week-old <i>Hyp</i> mice and wild-type (WT) control mice. The expression of <i>Fgf23</i>, <i>Dmp1</i>, and <i>Fam20c</i> was higher in osteocytic cells than in osteoblastic cells in both genotypes, and was up-regulated in <i>Hyp</i> cells. Interestingly, the up-regulation of these genes in <i>Hyp</i> bones began before birth. On the other hand, the expression of <i>Slc20a1</i> encoding the sodium/phosphate (Na⁺/Pi) co-transporter Pit1 was increased in osteoblasts and osteocytes from adult <i>Hyp</i> mice, but not in <i>Hyp</i> 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 <i>Fgf23</i> in WT osteoblastic cells but not in osteocytic cells. <i>Dmp1</i> 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 <i>Hyp</i> osteocytic cells, suggesting the activation of FGF/FGFR signaling. These results implicate the complex gene dysregulation in osteoblasts and osteocytes of <i>Hyp</i> mice, which might contribute to the pathogenesis.</p>