Overexpression of the DMP1 C-terminal fragment stimulates FGF23 and exacerbates the hypophosphatemic rickets phenotype in Hyp mice.
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abstract
Dentin matrix protein-1 (DMP1) or phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) inactivation results in elevation of the phosphaturic hormone fibroblast growth factor (FGF)-23, leading to hypophosphatemia, aberrant vitamin D metabolism, and rickets/osteomalacia. Compound mutant Phex-deficient Hyp and Dmp1(ko) mice exhibit nonadditive phenotypes, suggesting that DMP1 and PHEX may have interdependent effects to regulate FGF23 and bone mineralization. To determine the relative importance of DMP1 and PHEX in regulating FGF23 and mineralization, we tested whether the transgenic expression of full-length [Dmp1(Tg(full-length))] or C-terminal Dmp1 [Dmp1(Tg(57kDa))] could rescue the phenotype of Hyp mice. We found that Dmp1(ko) and Hyp mice have similar phenotypes characterized by decreased cortical bone mineral density (-35% vs. wild type, P < 0.05) and increased serum FGF23 levels (~12-fold vs. wild type, P < 0.05). This was significantly corrected by the overexpression of either the full-length or the C-terminal transgene in Dmp1(ko) mice. However, neither of the transgenes rescued the Hyp mice phenotype. Hyp/Dmp1(Tg(full-length)) and Hyp mice were similar, but Hyp/Dmp1(Tg(57 kDa)) mice exhibited worsening of osteomalacia (-20% cortical bone mineral density) in association with increased serum FGF23 levels (+2-fold) compared with Hyp mice. Bone FGF23 mRNA expression was decreased and a 2-fold increase in the ratio of the full-length/degraded circulating FGF23 was observed, indicating that degradation of FGF23 was impaired in Hyp/Dmp1(Tg(57 kDa)) mice. The paradoxical effects of the C-terminal Dmp1 transgene were observed in Hyp/Dmp1(Tg(57 kDa)) but not in Dmp1(Tg(57 kDa)) mice expressing a functional PHEX. These findings indicate a functional interaction between PHEX and DMP1 to regulate bone mineralization and circulating FGF23 levels and for the first time demonstrate effects of the C-terminal DMP1 to regulate FGF23 degradation.
