New insights into phosphate homeostasis: Fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia

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Abstract

Purpose of review: Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. Recent findings: Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In Hyp mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. Summary: In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.

Original languageEnglish (US)
Pages (from-to)547-553
Number of pages7
JournalCurrent Opinion in Nephrology and Hypertension
Volume11
Issue number5
DOIs
StatePublished - Sep 2002

Fingerprint

Osteomalacia
Homeostasis
Familial Hypophosphatemic Rickets
Phosphates
Hypophosphatemia
Neoplasms
Rickets
Familial Hypophosphatemia
Endopeptidases
fibroblast growth factor 23
FRZB protein
X Chromosome
Serum
Minerals
Peptide Hydrolases
Kidney
Enzymes

Keywords

  • Autosomal-dominant hypophosphatemic rickets
  • Hypophosphatemia
  • Rickets
  • Tumor-induced osteomalacia
  • X-linked hypophosphatemia

ASJC Scopus subject areas

  • Nephrology
  • Internal Medicine

Cite this

@article{005713db7b174e50a98f77360ba13ef8,
title = "New insights into phosphate homeostasis: Fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia",
abstract = "Purpose of review: Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. Recent findings: Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In Hyp mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. Summary: In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.",
keywords = "Autosomal-dominant hypophosphatemic rickets, Hypophosphatemia, Rickets, Tumor-induced osteomalacia, X-linked hypophosphatemia",
author = "Rajiv Kumar",
year = "2002",
month = "9",
doi = "10.1097/00041552-200209000-00011",
language = "English (US)",
volume = "11",
pages = "547--553",
journal = "Current Opinion in Nephrology and Hypertension",
issn = "1062-4821",
publisher = "Lippincott Williams and Wilkins",
number = "5",

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T1 - New insights into phosphate homeostasis

T2 - Fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia

AU - Kumar, Rajiv

PY - 2002/9

Y1 - 2002/9

N2 - Purpose of review: Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. Recent findings: Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In Hyp mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. Summary: In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.

AB - Purpose of review: Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. Recent findings: Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In Hyp mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. Summary: In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.

KW - Autosomal-dominant hypophosphatemic rickets

KW - Hypophosphatemia

KW - Rickets

KW - Tumor-induced osteomalacia

KW - X-linked hypophosphatemia

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