Distinguished roles of DMP1 and FGF23 in Odontogenesis

OBJECTIVES: DMP1, a matrix protein, is co-localized with FGF23, a newly identified hormone that inhibits Pi reabsorption in kidney, in the odontoblasts during development. Dmp1 null and FGF23 null mice display defects in odontogenesis during development. Yet, the local functions of these two molecules and their relationship are unknown. The goals of this study were to examine their local roles and possible interaction during odontogenesis using gene targeting approaches and neutralized antibodies against FGF23.

METHODS: 1) Dmp1 null, Fgf23 null and Dmp1-Fgf23 double KO and WT mice were sacrificed at age of 5 week-old; 2) Neutralizing antibodies against FGF23 were administered (i.p. injection) to Dmp1 null pups at age of 6-day for 9 days and animals were sacrificed for data analyses; 3) Combinations of serum biochemistry, histology, scanning electronic microscopy, radiograph and in situ hybridization methods were used to characterize tooth phenotype.

RESULTS: Similarities of tooth phenotypes between Fgf23 null and Dmp1 null mice are thin in dentin and large in pulp/root canal. The major differences of these null mice are Pi (high in Fgf23 null and low in Dmp1 null) and FGF23 levels (high in Dmp1 null and lack in Fgf23 null). Interestingly, FGF23 mRNA was sharply increased in Dmp1 null osteocytes but this change was moderate in Dmp1 null odontoblasts. Furthermore, the tooth phenotype was much worse, including very thin dentin with dentin fracture, and ectopic bone like structures appeared in pulp/root canal. The odontoblast layer is no longer polarized in double KO pulp area. Injections of neutralizing FGF23 ab completely restores Pi level to normal but the dentin phenotype remains, although significantly improved. Taken together, this study supports strong local roles of DMP1 and FGF23 during odontogenesis.

CONCLUSIONS: DMP1 and FGF23, with unique function, are required for odontogenesis. (Work supported by NIH grants: AR51587 and DE 016977)