# Role of modulators of Pi/PPi in cementum formation and regeneration

> **NIH NIH R00** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $249,000

## Abstract

ABST RACT
Proper pyrophosphate regulation is critical in mineralization processes. Pyrophosphate (PPi) is a direct
inhibitor of hydroxyapatite crystal growth, thus inhibiting mineralization. A main source of PPi is ATP, which is
hydrolyzed by ectonucleotide pyrophosphatase phosphodiesterases (ENPP), including ENPP1. ENPP1 is
expressed in bone along with progressive ankylosis protein (ANK), which transports intracellular PPi to
extracellular spaces. While ANK and ENPP1 increase extracellular PPi, tissue non-specific alkaline
phosphatase (TNAP, encoded by ALPL), hydrolyzes PPi into inorganic phosphate (Pi), thus decreasing PPi in
extracellular spaces. Although the specifics of direct or indirect interactions between ANK, ENPP1, and TNAP
are unknown, loss of any of these factors has dramatic effects on mineralized tissue. The studies proposed
here were developed to elucidate functions of pyrophosphate regulators with the ultimate goal of
developing therapies targeted toward mineralization disorders.
Abnormal PPi regulation (as exhibited by individuals with ENPP1, ANK or ALPL mutations) can lead to
alterations in the periodontium (cementum, periodontal ligament, alveolar bone), specifically cementum.
Alterations include excessive cementum formation (ENPP1, ANK) or deficient cementum formation leading to
premature tooth exfoliation (ALPL), an adverse sequelae of untreated periodontal disease. Periodontal
disease, a global burden with significant psychosocial and financial consequences, features destruction of the
periodontium. Existing regenerative therapies are unpredictable and do not target cementum regeneration. To
investigate roles of Ank and Enpp1 during cementogenesis, I, along with my colleagues, developed Ank,
Enpp1 double mutant mice. In preliminary studies, we noted a more dramatic hypercementosis phenotype in
8wk old Ank, Enpp1 double mutants versus single mutants. Additionally, we noted distinct differences between
single and double mutants within the PDL region/cementum in gene/protein expression of SIBLING proteins,
known modulators of the mineralization process. Three aims were developed to define ANK and ENPP1 roles
in periodontal development and maintenance, identify mechanistic pathways in which ANK and ENPP1
regulate cementogenesis (e.g. focused on direct and indirect ability to modulate SIBLINGs), and determine
the feasibility of using Enpp1 inhibitors to regenerate periodontaltissues.
As a clinician scientist, my ultimate goal is to conduct productive research that provides scientific insights into
periodontal disease pathogenesis and translate this knowledge into tangible clinical applications (e.g.
diagnostic/prognostic tests, prevention strategies, and therapeutic interventions). My career development plan
has been tailored toward this goal with solid mentorship, collaborations, and training opportunities in research
and clinical settings. In conjunction with institutional support, I am confident studies/activities outlined in...

## Key facts

- **NIH application ID:** 10480977
- **Project number:** 4R00DE031148-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Emily Yin Chu
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2021-09-14 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480977

## Citation

> US National Institutes of Health, RePORTER application 10480977, Role of modulators of Pi/PPi in cementum formation and regeneration (4R00DE031148-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10480977. Licensed CC0.

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