Dietary phosphate supplement does not rescue skeletal phenotype in a mouse model for craniometaphyseal dysplasia

J Negat Results Biomed. 2016 Oct 26;15(1):18. doi: 10.1186/s12952-016-0061-0.


Background: Mutations in the human progressive ankylosis gene (ANKH; Mus musculus ortholog Ank) have been identified as cause for craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. We previously reported a knock-in (KI) mouse model (Ank KI/KI) for CMD and showed transiently lower serum phosphate (Pi) as well as significantly higher mRNA levels of fibroblast growth factor 23 (Fgf23) in Ank KI/KI mice. FGF23 is secreted by bone and acts in kidney to promote Pi wasting which leads to lower serum Pi levels. Here, we examined whether increasing the Pi level can partially rescue the CMD-like skeletal phenotype by feeding Ank +/+ and Ank KI/KI mice with high Pi (1.7 %) diet from birth for 6 weeks. We studied the Pi metabolism in Ank KI/KI mice and CMD patients by examining the Pi regulators FGF23 and parathyroid hormone (PTH).

Results: High Pi diet did not correct CMD-like features, including massive jawbone, increased endosteal and periosteal perimeters and extensive trabeculation of femurs in Ank KI/KI mice shown by computed microtomography (μCT). This unexpected negative result is, however, consistent with normal serum/plasma levels of the intact/active form of FGF23 and PTH in Ank KI/KI mice and in CMD patients. In addition, FGF23 protein expression was unexpectedly normal in Ank KI/KI femoral cortical bone as shown by immunohistochemistry despite increased mRNA levels for Fgf23. Renal expression of genes involved in the FGF23 bone-kidney axis, including mFgfr1, mKlotho, mNpt2a, mCyp24a1 and m1αOHase, were comparable between Ank +/+ and Ank KI/KI mice as shown by quantitative real-time PCR. Different from normal FGF23 and PTH, serum 25-hydroxyvitamin D was significantly lower in Ank KI/KI mice and vitamin D insufficiency was found in four out of seven CMD patients.

Conclusions: Our data suggests that FGF23 signaling and Pi metabolism are not significantly affected in CMD and transiently low Pi level is not a major contributor to CMD.

Keywords: ANKH; Craniometaphyseal dysplasia; FGF23; Phosphate diet.

MeSH terms

  • Adolescent
  • Animals
  • Body Weight / drug effects
  • Bone Diseases, Developmental / blood
  • Bone Diseases, Developmental / drug therapy*
  • Bone Diseases, Developmental / genetics
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / drug effects
  • Bone and Bones / pathology*
  • Child
  • Craniofacial Abnormalities / blood
  • Craniofacial Abnormalities / drug therapy*
  • Craniofacial Abnormalities / genetics
  • Diet*
  • Dietary Supplements*
  • Disease Models, Animal
  • Female
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Hyperostosis / blood
  • Hyperostosis / drug therapy*
  • Hyperostosis / genetics
  • Hypertelorism / blood
  • Hypertelorism / drug therapy*
  • Hypertelorism / genetics
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Organ Size / drug effects
  • Parathyroid Hormone / blood
  • Phenotype
  • Phosphates / pharmacology
  • Phosphates / therapeutic use*
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood
  • X-Ray Microtomography


  • Parathyroid Hormone
  • Phosphates
  • Vitamin D
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • 25-hydroxyvitamin D

Supplementary concepts

  • Schwartz-Lelek syndrome