# Novel Control of FGF23 in Metabolic Bone Disease

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $228,772

## Abstract

Project Summary/Abstract: We identified Fibroblast growth factor-23 (FGF23) in a positional cloning
approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by
hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia and fracture. We made key
mechanistic connections regarding the regulation of FGF23 expression by crossover iron and phosphate
metabolism, showing that anemia caused late-onset ADHR in a mouse knock-in model of this disease.
These findings significantly modify the current endocrine feedback paradigms, determining that biological
stimuli outside of the known effectors of FGF23 control, namely anemia, could drive FGF23 production.
Therefore, the molecular mechanisms by which FGF23 is regulated and controls phosphate handling are
incompletely understood. This work is relevant to chronic kidney disease-mineral bone disorder (CKD-
MBD), the largest patient population with co-disturbances in phosphate handling (markedly increased
FGF23 leading to metabolic bone disease) and iron metabolism (progressive anemia as the kidneys fail)
leading to increased fracture risk and mortality. Our novel preliminary data now make a link between these
metabolic systems by demonstrating that erythropoietin (EPO) delivery, a cornerstone therapy for anemia in
CKD-MBD, markedly elevated bone Fgf23 mRNA and circulating FGF23 protein in mice. Further, these
increases occur by over-riding mechanisms that typically inhibit FGF23 production. Using a recently
developed mouse model carrying conditional flox-Fgf23 alleles, our initial findings also support that EPO
control of FGF23 may occur in bone cells outside of the ‘traditional’ expression sites of
osteoblasts/osteocytes, thus potentially revealing novel regulatory systems for phosphate metabolism. In
light of these new results, the molecular mechanisms dictating EPO-mediated FGF23 regulation during
kidney disease onset and progression, remain to be defined. The central hypothesis for this proposal is:
FGF23 is stimulated by EPO in osteoblasts/osteocytes and in hematopoietic progenitor cells leading to
altered mineral metabolism. This axis may be a modifiable risk factor in CKD-MBD, therefore we expect our
fundamental biological discoveries to provide novel translational insight into rare and common syndromes of
altered FGF23 expression, and into the basic biology of phosphate metabolism.

## Key facts

- **NIH application ID:** 9963210
- **Project number:** 5R01DK112958-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** KENNETH E WHITE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $228,772
- **Award type:** 5
- **Project period:** 2018-07-26 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963210

## Citation

> US National Institutes of Health, RePORTER application 9963210, Novel Control of FGF23 in Metabolic Bone Disease (5R01DK112958-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963210. Licensed CC0.

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