Date of Completion

6-24-2013

Embargo Period

8-31-2014

Keywords

craniofacial biology/genetics, mineralized tissue/development, ANKH, craniometaphyseal dysplasia, phosphate

Major Advisor

Ernst Reichenberger

Co-Major Advisor

Mina Mina

Associate Advisor

Peter Maye

Associate Advisor

Alexander Lichtler

Associate Advisor

Anne Delany

Associate Advisor

John Harrison

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Craniometaphyseal dysplasia (CMD) is a genetic disorder characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Mice carrying a knock-in mutation (Phe377del) in the Ank gene replicate many skeletal characteristics of human CMD including hyperostotic mandibles. A known function of the transmembrane protein ANK is to transport intracellular pyrophosphate (PPi) into the extracellular environment. PPi inhibits mineralization, while Pi promotes hydroxyapatite formation. A regulated Pi/PPi ratio is the key of physiological mineralization. Although the morphologies of erupted molars and incisors appear to be normal, AnkKI/KI mice have abnormal cervical loop positioning of the lower incisors and excessive cementum deposition of molars and incisors. The aim of this study was to investigate the mechanisms leading to abnormal tooth development in AnkKI/KI mice.

AnkKI/KI mice and Ank loss-of-function mouse models share similar cementum phenotype suggesting that altered Pi/PPi levels may increase cementum thickness. AnkKI/KI incisors erupt but show decreased eruption rate, decreased proliferation of odontoblast precursors and increased cell apoptosis in the stellate reticulum. However, their capability of continuous elongation is not compromised. Quantification of TRAP-positive cells in the apical end of AnkKI/KI incisors revealed decreased osteoclast numbers and osteoclast surface. Bisphosphonate injections in Ank+/+ mice replicate the AnkKI/KI incisor phenotype, suggesting that abnormal incisor elongation is secondary to reduced bone resorption.

In order to understand the contribution of Pi metabolism in the mandible and tooth development of the AnkKI/KI mice, mice were fed with a high or low Pi diet. High Pi diet exacerbated the mandibular hyperostosis whereas a low Pi diet decreased bone mass in AnkKI/KI mice. Both high and low Pi diets increased AnkKI/KI incisor dentin volume but did not change incisor length or cementum deposition.

We conclude that increased cementum thickness may be caused by an altered local Pi/PPi ratio and that the incisor phenotype is likely due to hyperostosis of mandibles. Furthermore, altered systemic Pi homeostasis appears to contribute to the mandibular hyperostosis but does not seem to affect incisor length or cementogenesis in the AnkKI/KI mice.

Download

Share

COinS