title: A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.
abstract: 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 by mutations 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-week-old Dmp1/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 low circulating intact Fgf23 levels with 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 by markedly 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 and maintains it through the regulation of Fgf23 cleavage and expression.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1120 West Michigan St, CL459, Indianapolis, IN, USA.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1120 West Michigan St, CL459, Indianapolis, IN, USA.
authors.forename: Rita L
authors.initials: RL
authors.lastname: Gerard-O'Riley
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1120 West Michigan St, CL459, Indianapolis, IN, USA.
authors.forename: Dena
authors.initials: D
authors.lastname: Acton
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1120 West Michigan St, CL459, Indianapolis, IN, USA.
authors.forename: Amie K
authors.initials: AK
authors.lastname: McQueen
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1120 West Michigan St, CL459, Indianapolis, IN, USA.
authors.forename: Isabel E
authors.initials: IE
authors.lastname: Strobel
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1120 West Michigan St, CL459, Indianapolis, IN, USA.
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Witcher
authors.affiliation: Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, Texas.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1120 West Michigan St, CL459, Indianapolis, IN, USA.|Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
mesh_terms: D000818:Animals; D015519:Bone Density; D045604:Extracellular Fluid / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D053098:Familial Hypophosphatemic Rickets / Q000097:blood / Q000235:genetics*; D005260:Female; D005269:Femur / Q000254:growth & development; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010710:Phosphates / Q000378:metabolism*
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23