# Hormonal and Molecular Etiology of Skeletal Abnormalities in XLH

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $367,511

## Abstract

The investigations in this proposal are directed at identifying the mechanism by which hypophosphatemia
leads to rickets, and the molecular basis for the therapeutic effectiveness of 1,25-dihydroxyvitamin D (1,25D) in
X-linked hypophosphatemia (XLH). While the combination of phosphate and 1,25D therapy for XLH has been
used for the past 4 decades, the molecular basis for the beneficial effects of 1,25D is not fully understood. We
have shown that monotherapy with 1,25D in the Hyp mouse model of XLH improves growth, prevents rickets
and improves the microarchitectural and biomechanical properties of bone despite doubling the already
increased circulating FGF23 levels. Despite this major increase in FGF23, 1,25D treatment significantly
decreases urinary phosphate in Hyp mice. Thus, 1,25D has beneficial effects on bone and renal phosphate
handling in XLH, in spite of further increasing FGF23. We propose to examine the effects of 1,25D on FGF23
signaling to identify the mechanism by which 1,25D antagonizes the phosphaturic effects of FGF23.
Preliminary data suggest that 1,25D causes retention of Npt2a/NHERF1 at renal brush border membranes of
Hyp mice by antagonizing FGF23 signaling downstream of FGF23/FGF receptor interactions. Studies will be
performed in kidneys, renal tubular cells and brush border membranes of WT and Hyp mice.
 Hypophosphatemia impairs hypertrophic chondrocyte apoptosis leading to rickets in growing animals and
humans, including those with XLH. We have shown that phosphate induction of ERK1/2 phosphorylation is
required for activation of the mitochondrial apoptotic pathway in hypertrophic chondrocytes in vitro and in vivo.
We have also shown that ablation of A-, B- and C-Raf in chondrocytes abolishes phosphate-induced ERK1/2
phosphorylation, impairs hypertrophic chondrocyte apoptosis and leads to rickets. Raf;MEK1/2;ERK1/2 can be
activated by several pathways. We, therefore, undertook a small molecule inhibitor screen to identify the
pathway by which phosphate induces ERK1/2 phosphorylation. These studies demonstrated that VEGFR
signaling is required for phosphate induced ERK1/2 phosphorylation in primary hypertrophic chondrocytes.
The studies proposed will address the hypothesis that phosphate activates VEGFR2 signaling specifically in
hypertrophic chondrocytes and will determine whether increased VEGFA release/secretion is required for
these effects. They will also address the hypothesis that chondrocyte-specific ablation of VEGFR2 impairs
phosphate-mediated hypertrophic chondrocyte apoptosis in vitro and normal growth plate maturation in vivo.
The effects of 1,25D on this signaling pathway will be examined to determine how 1,25D prevents rickets in the
setting of hypophosphatemia. Thus, the studies proposed will identify the molecular basis for induction of
hypertrophic chondrocyte apoptosis by phosphate and will define how 1,25D modulates this process and
impairs the phosphaturic effects of FGF23 in the kidney. Our studies wi...

## Key facts

- **NIH application ID:** 9985727
- **Project number:** 5R01AR072650-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Marie Demay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,511
- **Award type:** 5
- **Project period:** 2017-09-21 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985727

## Citation

> US National Institutes of Health, RePORTER application 9985727, Hormonal and Molecular Etiology of Skeletal Abnormalities in XLH (5R01AR072650-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985727. Licensed CC0.

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