# Role of tissue-nonspecific alkaline phosphatase in dentoalveolar development and disease

> **NIH NIH R03** · OHIO STATE UNIVERSITY · 2020 · $156,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Tissue-nonspecific alkaline phosphatase (TNAP) is perhaps the most critical enzyme for skeletal and dental
mineralization, reducing local concentrations of the mineralization inhibitor, inorganic pyrophosphate (PPi). Loss-
of-function mutations in the TNAP-encoding ALPL gene cause hypophosphatasia (HPP), an inherited error-of-
metabolism that causes rickets, osteomalacia, and bone fragility. Dental defects accompanying HPP are lifelong
difficulties, the most common being premature tooth loss. Dental tissues are among the most sensitive to HPP,
as dental manifestations are nearly universal in HPP subjects. The recently approved TNAP enzyme
replacement therapy (ERT) shows great promise for improving skeletal mineralization and overall health,
however, critical gaps in knowledge present obstacles to understanding pathological mechanisms and
successful treatment of HPP dental disease. The long-term goals of our studies are to better understand how
HPP affects dentoalveolar tissues and use that knowledge to direct evidence-based treatment, also informing
about the larger functional importance of TNAP in development and potential for use in regenerative therapies.
To begin to accomplish these goals, our short term aims are: for the first time to directly and quantitatively analyze
effects of HPP on dental tissues in human teeth, and to use a novel mouse model of HPP to investigate efficacy
of ERT on dentoalveolar tissues based on time of intervention. Our central hypotheses, based on previous
reports and our preliminary data, are that all dental hard tissues are affected by HPP in a manner correlated to
severity of skeletal/systemic/biochemical changes, and that ERT can correct the course of dentoalveolar
mineralization and tooth attachment in HPP. Our hypotheses will be tested by two Specific Aims: (1) Quantify
HPP dental mineralization defects and correlate with other phenotype manifestations in humans and mice; and
(2) Analyze effects of enzyme replacement therapy (ERT) on human teeth and HPP mouse dentoalveolar
development and function. Innovations in our study design will address gaps in knowledge related to HPP and
TNAP in dentoalveolar development and function. These innovations arise from coordinated application of novel
tools and unique opportunities, including: the first use of high resolution micro-CT and histological analysis on a
large collection of teeth from HPP subjects, also correlating dental data to musculoskeletal, biochemical, and
genetic analyses in that cohort; the first analysis of teeth from HPP subjects treated with ERT; optimization of a
novel mouse model of HPP to test ERT at timed interventions at later more clinically relevant ages; first use of
an orthodontic tooth movement model to evaluate periodontal response in ERT-treated HPP mice; and first use
of mechanical testing to evaluate periodontal function in treated genetically modified mice. Future Research
Plans: Experiments will provide data for...

## Key facts

- **NIH application ID:** 9971507
- **Project number:** 5R03DE028411-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Brian Lee Foster
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971507

## Citation

> US National Institutes of Health, RePORTER application 9971507, Role of tissue-nonspecific alkaline phosphatase in dentoalveolar development and disease (5R03DE028411-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9971507. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*