# The role of DMP1 in FGF23-induced hypophosphatemia

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $633,702

## Abstract

PROJECT SUMMARY
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone. Hypophosphatemic rickets
disorders, such as X-linked hypophosphatemia (XLH) and autosomal recessive hypophosphatemic rickets
(ARHR), are associated with FGF23 excess, impaired skeletal growth and osteomalacia leading to debilitating
bone pain and fractures. New therapy consisting in FGF23 antibody injections to increase serum phosphate (Pi)
levels in XLH improves bone growth and mineralization. However, further studies are needed to determine if
this strategy is efficacious in the long term and in other diseases associated with FGF23 excess, including ARHR.
XLH and ARHR type I are respectively caused by inactivating mutations of Pi regulating gene with homologies
to endopeptidase X-linked (PHEX) and dentin matrix protein (DMP1) that work in concert to regulate FGF23
production. In preliminary data for this project, we show that (1) FGF23 excess and hypophosphatemia
contribute to the bone defects in mice with ARHR, (2) excess FGF23 and parathryroid hormone are not solely
responsible for renal Pi wasting, (3) DMP1 directly stimulates Pi reabsorption in the kidney, (4) PHEX and DMP1
are expressed in renal tubular cells where Pi reabsorption occurs, and (5) loss of kidney PHEX induces
phosphaturia and bone loss despite increased DMP1 and low FGF23 levels. The goal of this project is to
investigate the pathogenesis of hypophosphatemia induced by DMP1 deficiency.
In Aim 1, we will define the contribution of FGF23 excess and hypophosphatemia to impaired bone mineralization
in mice with ARHR. We will use normal and high dietary Pi administration, and genetic deletion of Fgf23 in wild-
type (WT) and Dmp1KO to assess modifications of bone and mineral metabolism in mice and cultured primary
osteoblasts over time. In Aim 2, we will establish the role of DMP1 in stimulating Pi reabsorption by antagonizing
FGF23-FGFR1 signaling in the kidney. We will use normal and high dietary Pi administration, and genetic
overexpression of Fgf23 or deletion of Fgfr1, in WT mice and in animals with genetic overexpression of Dmp1
(Dmp1TG). We will assess bone and mineral metabolism, Pi intake and excretion, kidney function and FGFR1
activation in the kidney, in presence of elevated FGF23 and DMP1 levels. Finally, in Aim 3, we will investigate
the contribution of kidney DMP1 deficiency to the pathophysiology of ARHR and XLH by performing kidney
transplants between Dmp1TG and Dmp1KO and between WT, Hyp and Dmp1TG donor and recipient mice. We
will establish whether kidney-expressed DMP1 is required to fully correct hypophosphatemia in mice with ARHR,
and if loss of kidney PHEX function is sufficient to induce hyperphosphaturia and bone loss despite elevated
DMP1 and low FGF23 levels. This will demonstrate a key functional interaction between PHEX and DMP1 in the
kidney. These innovative aims are supported by a productive collaborative team at Northwestern University that
will further ...

## Key facts

- **NIH application ID:** 10423167
- **Project number:** 1R01DK132342-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Aline C Martin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $633,702
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10423167

## Citation

> US National Institutes of Health, RePORTER application 10423167, The role of DMP1 in FGF23-induced hypophosphatemia (1R01DK132342-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10423167. Licensed CC0.

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