Pathogenic role of Fgf23 in Dmp1-null mice

Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E254-61. doi: 10.1152/ajpendo.90201.2008. Epub 2008 Jun 17.


Autosomal recessive hypophosphatemic rickets (ARHR), which is characterized by renal phosphate wasting, aberrant regulation of 1alpha-hydroxylase activity, and rickets/osteomalacia, is caused by inactivating mutations of dentin matrix protein 1 (DMP1). ARHR resembles autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH), hereditary disorders respectively caused by cleavage-resistant mutations of the phosphaturic factor FGF23 and inactivating mutations of PHEX that lead to increased production of FGF23 by osteocytes in bone. Circulating levels of FGF23 are increased in ARHR and its Dmp1-null mouse homologue. To determine the causal role of FGF23 in ARHR, we transferred Fgf23 deficient/enhanced green fluorescent protein (eGFP) reporter mice onto Dmp1-null mice to create mice lacking both Fgf23 and Dmp1. Dmp1(-/-) mice displayed decreased serum phosphate concentrations, inappropriately normal 1,25(OH)(2)D levels, severe rickets, and a diffuse form of osteomalacia in association with elevated Fgf23 serum levels and expression in osteocytes. In contrast, Fgf23(-/-) mice had undetectable serum Fgf23 and elevated serum phosphate and 1,25(OH)(2)D levels along with severe growth retardation and focal form of osteomalacia. In combined Dmp1(-/-)/Fgf23(-/-), circulating Fgf23 levels were also undetectable, and the serum levels of phosphate and 1,25(OH)(2)D levels were identical to Fgf23(-/-) mice. Rickets and diffuse osteomalacia in Dmp1-null mice were transformed to severe growth retardation and focal osteomalacia characteristic of Fgf23-null mice. These data suggest that the regulation of extracellular matrix mineralization by DMP1 is coupled to renal phosphate handling and vitamin D metabolism through a DMP1-dependent regulation of FGF23 production by osteocytes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Density
  • Calcification, Physiologic
  • Calcitriol / blood
  • Extracellular Matrix Proteins / deficiency*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Familial Hypophosphatemic Rickets / blood
  • Familial Hypophosphatemic Rickets / genetics
  • Familial Hypophosphatemic Rickets / metabolism*
  • Femur / metabolism
  • Femur / pathology
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / blood
  • Fibroblast Growth Factors / deficiency
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Genetic Diseases, X-Linked*
  • Male
  • Mice
  • Mice, Knockout
  • Osteomalacia / blood
  • Osteomalacia / genetics
  • Osteomalacia / metabolism*
  • Phosphates / blood
  • RNA / chemistry
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rickets / blood
  • Rickets / genetics
  • Rickets / metabolism*


  • Dmp1 protein, mouse
  • Extracellular Matrix Proteins
  • Fgf23 protein, mouse
  • Phosphates
  • Fibroblast Growth Factors
  • RNA
  • Fibroblast Growth Factor-23
  • Calcitriol