Three-dimensional Analysis of PFE in Mouse and Human

Objectives: Primary failure of eruption (PFE) is a rare genetic disorder that exclusively hampers tooth eruption process. It has been reported that the underlying cause of this disorder in human is the loss-of-function mutations in parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1(PTH/PTHrP receptor, PPR). Our previous study showed that in a mouse PFE model, PTHrP-PPR signaling is responsible for orchestrating normal dental follicle cell differentiation and tooth eruption. However, the mechanism underlying the infra-eruption of tooth in PFE remains elusive due to the lack of long-term studies. Our objective is to chronologically observe tooth eruption and tooth morphology of mouse PFE molars through 3D-micro CT analyses.
Methods: Two patients with pathogenic mutation in the PTH1R gene were recruited from Showa University and radiological images were acquired by CBCT. A mouse PFE model was generated by conditionally deleting PPR in PTHrP-expressing dental follicular cells using PTHrP-creER and PPR floxed alleles. Mouse samples were then divided into three groups, PPR^fl/fl;R26R^tdTomato/+(Control), PTHrP-creER;PPR^fl/+;R26R^tdTomato/+(cHet) and PTHrP-creER;PRR^fl/fl;R26R^tdTomato/+(cKO). Single-dose of Tamoxifen were injected at postnatal day (P)3 and samples were collected at P 14, 25, 91 and 182. Finally, superimposition of images and 3D-micro CT analyses among groups were rendered and statistically analyzed.
Results: Mouse and human PFE showed similar defects in 3D analyses. The quantitative analysis in mice showed a significant reduction in eruption height of cKO first and second molars compare to control and cHet samples starting from P 25 to 182. In addition, cKO first molars exhibited significant shorter roots with dilacerations after P 25. Lastly, the interradicular bone height of knockout mice at P182 is significantly decreased.
Conclusions: PFE mouse molars demonstrated delayed tooth eruption compare to normal molars. Additionally, shorten and dilacerated root associated with defective interradicular bones were exhibited in PFE molars.