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.

Physiological Actions of Fibroblast Growth Factor-23

“…ARHR1 is caused by loss-of-function mutations in dentin matrix protein-1, which is required for normal mineralization of bone ( 18 ). It is currently believed that the excessive osteocytic and osteoblastic FGF23 secretion in both diseases is either driven by the impaired mineralization of the extracellular matrix, which may be detected by matrix-embedded bone cells through a putative sensing mechanism that may involve FGF receptors ( 19 , 20 ), or by an altered set point for phosphate sensing in bone cells ( 21 , 22 ). Circulating intact FGF23 is also elevated in patients with chronic kidney disease (CKD), and can reach blood levels as high as 1,000-fold above the normal range ( 23 , 24 ).…”

Genetic Knockout and Rescue Studies in Mice Unravel Abnormal Phosphorus Threshold in Hypophosphatemic Rickets

“…Activating mutation in the Phex gene, the most common cause of hypophosphatemic rickets, occurs in 1:20,000 people and is inherited as X-linked ( 7 ). The common abnormality reported in both X-linked and autosomal recessive hypophosphatemic rickets is an increase in circulating FGF23 due to enhanced skeletal expression as demonstrated by Ichikawa et al ( 15 ) in the current issue of Endocrinology as well as by others. FGF23 interacts with the FGF receptor and Klotho to promote mitogen-activated protein kinase signaling and, thereby, decrease expression of Npt2a and Npt2c in renal tubular cells.…”

“…In a study published in the current issue of Endocrinology (15), Econs and colleagues addressed the question of whether the set point for phosphate is also lowered in ARHR by using Dmp1 knockout mice, a murine model of ARHR. In the current study, the authors reported the presence of the same low extracellular phosphorus set point in Dmp1 null mice with the associated increase in both circulating and skeletal expression of Fgf23 .…”

“…In a previous study, Econs and colleagues ( 17 ) demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, which further stimulates FGF23 production to maintain lower serum phosphate levels. In a study published in the current issue of Endocrinology ( 15 ), Econs and colleagues addressed the question of whether the set point for phosphate is also lowered in ARHR by using Dmp1 knockout mice, a murine model of ARHR. In the current study, the authors reported the presence of the same low extracellular phosphorus set point in Dmp1 null mice with the associated increase in both circulating and skeletal expression of Fgf23 .…”

Iron Chelation Resulting in Renal Phosphate Wasting

“…The exact role of DMP1 remains unknown, but recent murine experimental models have shown that mutations in the DMP1 gene create a lower set point for extracellular phosphate and maintain it through the regulation of FGF23 cleavage and expression. 11 …”