# Renal regulation of phosphate homeostasis and its effect on bone

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $407,597

## Abstract

PROJECT SUMMARY/ABSTRACT
Continuously elevated parathyroid hormone (PTH) causes hypercalcemia/hypophosphatemia and
enhances bone turnover. This results in bone loss because bone resorption increases more prominently
than bone formation. In contrast, daily PTH injection enhances bone formation with only transient mineral
ion changes. Surprisingly, mice expressing a constitutively active PTH/PTHrP receptor (PTHR1) in bone
(Col1-H223R or Dmp1-H223R) show profound bone mass increases. Likewise, patients affected by
pseudohypoparathyroidism (PTH-resistance in kidney, but not in bone), treated with calcium and 1,25(OH)2
vitamin D (1,25D), can show a major increase in bone formation, despite elevated PTH levels. Findings in
transgenic mice and a human disease thus suggested that persistent PTHR1 activation can increase bone
mass, if excess urinary phosphate excretion is prevented. Considerable evidence indicates that urinary
phosphate excretion by PTH depends not only on cAMP/PKA signaling, but also on IP3/PKC-dependent
mechanisms. In fact, D/D mice expressing a phospholipase C (PLC)-deficient PTHR1 do not sustain
phosphate excretion when the PTHR1 is continuously activated. Furthermore, wild-type animals receiving
long-term infusions of [Trp1]PTH(1-34), a biased PTH analog with impaired IP3 signaling, failed to sustain
phosphate excretion and 1,25D production. In addition to its renal importance, PTH-stimulated
PLC/IP3/PKC signaling is required for bone formation. For example, tibiae of wild-type mice undergoing
prolonged PTH-dependent PTHR1 activation showed rapid expansion of fibroblast-like stromal bone (FSB)
cells; such osteoblast precursors were not observed in D/D mice with continuous PTH elevations and in
wild-type mice infused with [Trp1]PTH(1-34), thus supporting the conclusion that PLC-signaling at the
PTHR1 is required for normal bone formation. We will now determine whether persistent IP3/PKC-signaling
at the PTHR1 is required for long-term regulation of phosphate homeostasis and 1,25D production, and
whether continuous PTHR1 activation can enhance bone formation, if excess urinary phosphate excretion
can be prevented. Two aims will be pursued: Aim 1 will explore further whether PTH-dependent IP3/PKC
signaling is required for sustained phosphate excretion, for 1,25D production, and for expansion of
osteoblast precursors. Aim 2 will determine whether the high bone mass in Col1-H223R mice and animals
with osteocyte-specific SIK2/3 ablation can be reversed by promoting renal phosphate excretion through
PTH-independent interventions, namely through a novel NPT2a inhibitor or through recombinant FGF23.
We will also determine whether “bone-seeking” PTH analogs can induce bone formation because of
continuous local PTHR1 activation, yet limited renal actions, i.e. no phosphaturia and no 1,25D increase.
Our investigations will help clarify further the role of PLC-dependent PTHR1 signaling in kidney and bone,
and the importance of phosphate in mainta...

## Key facts

- **NIH application ID:** 10434874
- **Project number:** 5P01DK011794-54
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** HARALD W. JUEPPNER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $407,597
- **Award type:** 5
- **Project period:** 1997-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434874

## Citation

> US National Institutes of Health, RePORTER application 10434874, Renal regulation of phosphate homeostasis and its effect on bone (5P01DK011794-54). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434874. Licensed CC0.

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