A mutation in the Dmp1 gene alters phosphate responsiveness in mice

Shoji Ichikawa, Rita L. Gerard-O'Riley, Dena Acton, Amie K. McQueen, Isabel E. Strobel, Phillip C. Witcher, Jian Q. Feng, Michael J. Econs

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8 Scopus citations


Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused bymutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-weekoldDmp1/Galnt3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), Galnt3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. Galnt3 knockout mice had increased proteolytic cleavage of Fgf23, leading to lowcirculating intact Fgf23 levelswith consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the Galnt3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied bymarkedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate andmaintains it through the regulation of Fgf23 cleavage and expression.

Original languageEnglish (US)
Pages (from-to)470-476
Number of pages7
Issue number3
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Endocrinology

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    Ichikawa, S., Gerard-O'Riley, R. L., Acton, D., McQueen, A. K., Strobel, I. E., Witcher, P. C., Feng, J. Q., & Econs, M. J. (2017). A mutation in the Dmp1 gene alters phosphate responsiveness in mice. Endocrinology, 158(3), 470-476. https://doi.org/10.1210/en.2016-1642