Dietary phosphate restriction normalizes biochemical and skeletal abnormalities in a murine model of tumoral calcinosis

Shoji Ichikawa, Anthony M. Austin, Amie K. Gray, Matthew Allen, Michael Econs

Research output: Contribution to journalArticle

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Abstract

Mutations in the GALNT3 gene cause tumoral calcinosis characterized by ectopic calcifications due to persistent hyperphosphatemia. We recently developed Galnt3 knockout mice in a mixed background, which had hyperphosphatemia with increased bone mineral density (BMD) and infertility in males. To test the effect of dietary phosphate intake on their phenotype, Galnt3 knockout mice were generated in the C57BL/6J strain and fed various phosphate diets: 0.1% (low), 0.3% (low normal), 0.6% (normal), and 1.65% (high). Sera were analyzed for calcium, phosphorus, alkaline phosphatase, creatinine, blood urine nitrogen, 1,25-dihydroxyvitamin D, osteocalcin, tartrateresistant acid phosphatase 5b, and fibroblast growth factor 23 (Fgf23). Femurs were evaluated by dual-energy x-ray absorptiometry, dynamic histomorphometry, and/or microcomputed tomography. Galnt3 knockout mice in C57BL/6J had the same biochemical phenotype observed in our previous study: hyperphosphatemia, inappropriately normal 1,25-dihydroxyvitamin D level, decreased alkaline phosphatase activity, and low intact Fgf23 concentration but high Fgf23 fragments. Skeletal analyses of their femurs revealed significantly high BMD with increased cortical bone area and trabecular bone volume. On all four phosphate diets, Galnt3 knockout mice had consistently higher phosphorus levels and lower alkaline phosphatase and intact Fgf23 concentrations than littermate controls. The low-phosphate diet normalized serum phosphorus, alkaline phosphatase, and areal BMD but failed to correct male infertility in Galnt3 knockout mice. The high-phosphate diet did not increase serum phosphorus concentration in either mutant or control mice due to a compensatory increase in circulating intact Fgf23 levels. In conclusion, dietary phosphate restriction normalizes biochemical and skeletal phenotypes of Galnt3 knockout mice and, thus, can be an effective therapy for tumoral calcinosis.

Original languageEnglish
Pages (from-to)4504-4513
Number of pages10
JournalEndocrinology
Volume152
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Calcinosis
Knockout Mice
Phosphates
Hyperphosphatemia
Phosphorus
Alkaline Phosphatase
Bone Density
Diet
Male Infertility
Phenotype
Femur
Serum
X-Ray Microtomography
Osteocalcin
Acid Phosphatase
Creatinine
Nitrogen
X-Rays
fibroblast growth factor 23
Urine

ASJC Scopus subject areas

  • Endocrinology

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Dietary phosphate restriction normalizes biochemical and skeletal abnormalities in a murine model of tumoral calcinosis. / Ichikawa, Shoji; Austin, Anthony M.; Gray, Amie K.; Allen, Matthew; Econs, Michael.

In: Endocrinology, Vol. 152, No. 12, 12.2011, p. 4504-4513.

Research output: Contribution to journalArticle

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