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Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D₃

Departments of ¹Human Genetics, ³Medicine, ⁵Pediatrics, and ⁴Physiology, McGill University, and ²The McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada H3Z 2Z3

Submitted 5 September 2003 ; accepted in final form 16 December 2003

Mutations in the PHEX gene are responsible for X-linked hypophosphatemia, a renal phosphate-wasting disorder associated with defective skeletal mineralization. PHEX is predominantly expressed in bones and teeth and in the parathyroid gland of patients with chronic renal failure and tertiary hyperparathyroidism. The purpose of the present study was to examine the effects of renal insufficiency and 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] on the regulation of PHEX expression in rat tibia and parathyroid gland. In rats fed a high-phosphate (P_i) diet, nephrectomy elicited a significant increase in the serum parathyroid hormone (PTH) concentration that was associated with a significant increase in the abundance of PHEX mRNA and protein in the tibia and a significant increase in PHEX mRNA in the parathyroid gland. In contrast, 1,25(OH)₂D₃ administration to intact rats fed a control diet elicited a significant decrease in the serum PTH concentration that was accompanied by a significant decrease in PHEX mRNA and protein abundance in the tibia and a significant decrease in PHEX mRNA in the parathyroid gland. In addition, the increases in serum PTH levels and PHEX mRNA in the tibia and parathyroid gland in nephrectomized rats fed a high-P_i diet were blunted by 1,25(OH)₂D₃. Serum PTH concentration was positively and significantly correlated with tibial PHEX mRNA and protein abundance. In summary, we demonstrate that PHEX expression in the tibia and parathyroid gland is increased by chronic renal insufficiency and decreased by 1,25(OH)₂D₃ administration and suggest that PTH status may play an important role in mediating these changes in PHEX expression.

parathyroid hormone; hyperphosphatemia; endopeptidase

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