# Phosphate signaling in biomineralization

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $329,903

## Abstract

Abstract
Inorganic phosphate (PO43-/Pi) is a critical regulator of the physiologic biomineralization process in skeletal and
dental tissues, and is a major contributing factor to pathologic mineralization of blood vessels. The central role
of Pi in biomineralization is underscored by a broad-range of mineralization defects in genetic and acquired
disorders affecting systemic Pi homeostasis (hyperphosphatemia and hypophosphatemia) and local/cellular Pi
availability (e.g. hypophosphatasia). Although it is well established now that Pi is a signaling molecule that can
change cellular physiology, the underlying molecular mechanisms by which Pi executes this function remain
largely unknown. This gap in our knowledge impedes development of targeted therapeutic approaches to
diseases caused by abnormal Pi availability. Our goal is to delineate the signaling cascade that regulates
biomineralization in response to extracellular Pi. We and others have shown that molecular interactions
upstream of Erk1/2 kinase are central to initiating the response to extracellular Pi in the majority of analyzed
cells. Our preliminary studies in cells producing mineralized extracellular matrix (osteogenic cells) identified a
molecular circuit, which is required for activation of Erk1/2 and mineralization-supporting functions in response
to Pi. First, our in vitro data show that osteogenic cells deficient in parathyroid hormone/parathyroid hormone
related protein receptor 1 (Pth1r) do not activate Erk1/2 under high Pi conditions and have significantly
impaired transcriptional response to Pi. Second, our data suggest that Pi-induced Erk1/2 activation and gene
expression are dependent on the protein kinase C (PKC). Furthermore, our data suggest that the cellular
response to Pi is enhanced by calcium (Ca2+). Based on these data we hypothesize that the Pi-induced
signaling cascade is integrated with the Pth1r-PKC-Erk1/2 pathway in osteogenic cells. To test this hypothesis
we will use in vitro and in vivo approaches focused on signaling in cells producing mineralized extracellular
matrix. In the Aim 1 of this project, we will define the molecular circuit of Pth1r-dependent activation of cellular
responses to Pi. In the Aim 2, we will determine the functional role of Pth1r in Pi signaling and Pi-regulated
mineralization in vivo. In the Aim 3, we will determine the role of Ca2+ in mineralization-supporting functions of
Pi signaling. By completing these Aims, will provide the first characterization of the Pi-induced signaling
cascade and identify molecular players required for initiation of cellular responses to Pi in osteogenic cells.
This will provide the foundation for identification of targets for pharmacological regulation of cellular sensitivity
to available Pi.

## Key facts

- **NIH application ID:** 10177871
- **Project number:** 5R01AR074981-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Dobrawa Napierala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,903
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177871

## Citation

> US National Institutes of Health, RePORTER application 10177871, Phosphate signaling in biomineralization (5R01AR074981-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10177871. Licensed CC0.

---

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