# Pharmacological rescue of tooth eruption disorders

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $462,810

## Abstract

Project Summary / Abstract
A healthy dentition with appropriately functioning teeth is essential for maintaining quality of life (QOL).
Disorders involving tooth eruption are prevalent, as high as 2–4% in permanent molars alone. Multiple molars
are involved in severe cases such as rare genetic conditions of primary failure of tooth eruption (PFE) or, more
commonly, bisphosphonate-induced arrest of tooth eruption in pediatric patients, which significantly
compromise the patients' ability to chew effectively. Because these molars do not response well to
conventional orthodontic approaches, innovative adjuvant therapies are needed to restore tooth eruption of
affected molars for better clinical outcomes. Tooth eruption is regulated by cells in the dental follicle (DF)
surrounding developing molars, which express parathyroid hormone-related protein (PTHrP) and its cognate
PTH/PTHrP receptor (PTH1R). Disruption of autocrine PTHrP-PTH1R signaling in PTHrP+ DF cells causes
failure of tooth eruption in murine molars that closely recapitulates the human PFE condition. Salt inducible
kinases (SIKs) are an essential downstream effector of PTH1R-cAMP/PKA signaling in bone, in which cAMP-
regulated PKA-dependent SIK inhibition is a key component of the anabolic actions of PTH. Small molecules
SIK inhibitors hold promise as a novel therapeutic strategy to enhance cAMP-induced signals in a receptor-
independent manner. In this proposal, we hypothesize that activation of the PTH1R signaling pathway by direct
SIK inhibition can restore defective tooth eruption of molars in mouse models of genetically and
pharmacologically induced tooth eruption disorders. In Aim 1, we will identify the roles of SIKs in PTHrP+ dental
follicle cells in tooth eruption. We hypothesize that SIKs regulate osteoblast cell fates of PTHrP+ DF cells and
tooth eruption. We will define the function of SIK2/SIK3 by conditionally deleting these genes in PTHrP+ DF
cells at the onset of tooth eruption. We will define short-term and long-term alterations in tooth eruption and
tooth root structures of mutant molars using histological and 3D microCT analyses. In Aim 2, we will determine
the effects of SIK inhibition in rescuing PFE in molars. We hypothesize that SIK inhibition rescues failure of
tooth eruption in molars genetically caused by PTH1R deficiency. We will determine the effects of SIK
inhibition in a mouse model of PFE, in which PTH1R is conditionally deleted in PTHrP+ DF cells at the onset of
tooth eruption. We will investigate whether PFE phenotypes can be rescued genetically by a concomitant loss
of SIK2/SIK3, and pharmacologically by SIK inhibitor YKL-05-099. In Aim 3, we will define PTHrP as a
bisphosphonate target and effects of SIK inhibitors in rescuing tooth eruption. We hypothesize that PTHrP-
PTH1R signaling is altered in PTHrP+ DF cells in response to zoledronic acid (ZOL), and ZOL-induced arrest of
tooth eruption in molars can be rescued by SIK inhibitors. We will treat ZOL-...

## Key facts

- **NIH application ID:** 10887457
- **Project number:** 5R01DE030416-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Wanida Ono
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $462,810
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887457

## Citation

> US National Institutes of Health, RePORTER application 10887457, Pharmacological rescue of tooth eruption disorders (5R01DE030416-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10887457. Licensed CC0.

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