# Role of HNF4a in the regulation of FGF23 in health and disease

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $395,000

## Abstract

PROJECT SUMMARY
Patients with chronic kidney disease (CKD) experience a wide-range of bone and mineral metabolism
abnormalities, including bone mass loss and excess production of fibroblast growth factor 23 (FGF23) by
osteocytes. Serum FGF23 levels rise early in the course of CKD, and high levels are independently associated
with greater risks of CKD progression, cardiovascular disease and death. These findings have stimulated interest
in designing therapies to reduce bone abnormalities and lower FGF23 levels, but the approach is limited by poor
understanding of the molecular mechanisms at play. In preliminary data of this proposal, we show that the
nuclear receptor, hepatocyte nuclear factor 4 alpha (HNF4α) is mechanistically linked to bone specific pathways
controlling FGF23 production in animal models of FGF23 excess. We also show that FGF23 promoter contains
a predicted HNF4 response element (HNF4-RE) and that Hnf4α is expressed in osteoblasts and osteocytes. In
new preliminary data, we show that HNF4α stimulates osteoblast proliferation and that osteoblast specific
deletion of Hnf4α leads to FGF23 excess in osteoblasts and mice, and to low bone mass in animals. We also
show that Hnf4α expression is repressed by 98% in bones from an established model of progressive CKD, the
Col4a3KO mouse. These observations support an important new role for HNF4α. In this proposal, we will test the
hypothesis that HNF4α deficiency in CKD contributes to excess FGF23 and bone abnormalities. In Aim1 we
will establish the role of HNF4α in bone, by assessing in vitro the proliferation, activity and differentiation of
osteoblasts that overexpress or lack HNF4α. We will characterize the bone HNF4α transcriptome by RNA
sequencing and complete the bone phenotype analysis of mice carrying the specific deletion of Hnf4α in
osteoblasts/osteocytes (Hnf4αOc-cKO). To investigate whether HNF4α mediates the osteogenic response, we will
expose WT and Hnf4αOc-cKO mice to catabolic and anabolic PTH challenges. In Aim2 we will investigate HNF4α
as a molecular suppressor of FGF23 production in bone, by testing whether HNF4α directly binds to HNF4-RE
on FGF23 promoter to inhibit FGF23 transcription. We will also determine FGF23 response to HNF4α inhibition
in mice with low FGF23 production. Finally, in Aim3 we will test the hypothesis that in CKD, decreased HNF4α
activation stimulates FGF23 transcription. We will determine when HNF4α expression decreases during CKD
progression and whether HNF4α responds to phosphate. We will demonstrate the therapeutic potential of
targeting HNF4α pathways by crossing Col4a3KO to newly generated mice containing a bone targeted
overexpression of Hnf4α (HNF4αOc-cTg) and by assessing correction of FGF23 levels and bone mass in
Col4a3KO/Hnf4αOc-cTg compound mice. The project will contribute to new insights into the molecular regulation of
bone and FGF23 in health and in CKD, and support our ultimate goal of developing novel therapeutic approaches
to i...

## Key facts

- **NIH application ID:** 10129952
- **Project number:** 5R01DK114158-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Nicolae Valentin David
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129952

## Citation

> US National Institutes of Health, RePORTER application 10129952, Role of HNF4a in the regulation of FGF23 in health and disease (5R01DK114158-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129952. Licensed CC0.

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