FGF23 and its role in X-linked hypophosphatemia-related morbidity

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Abstract

Background

X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked ( PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood.

Methods

The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH.

Results

The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations.

Conclusions

By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.

Related collections

Most cited references 220

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Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.

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Proper serum phosphate concentrations are maintained by a complex and poorly understood process. Identification of genes responsible for inherited disorders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disorders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets (XLH), hypophosphataemic bone disease (HBD), hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and autosomal dominant hypophosphataemic rickets (ADHR). Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH (refs 6,7). ADHR (MIM 193100) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses. Here we describe a positional cloning approach used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23. These mutations in patients with ADHR represent the first mutations found in a human FGF gene.

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T Shimada, S Mizutani, T Muto … (2001)

Tumor-induced osteomalacia (TIO) is one of the paraneoplastic diseases characterized by hypophosphatemia caused by renal phosphate wasting. Because removal of responsible tumors normalizes phosphate metabolism, an unidentified humoral phosphaturic factor is believed to be responsible for this syndrome. To identify the causative factor of TIO, we obtained cDNA clones that were abundantly expressed only in a tumor causing TIO and constructed tumor-specific cDNA contigs. Based on the sequence of one major contig, we cloned 2,270-bp cDNA, which turned out to encode fibroblast growth factor 23 (FGF23). Administration of recombinant FGF23 decreased serum phosphate in mice within 12 h. When Chinese hamster ovary cells stably expressing FGF23 were s.c. implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. In addition, a high level of serum alkaline phosphatase, low 1,25-dihydroxyvitamin D, deformity of bone, and impairment of body weight gain became evident. Histological examination showed marked increase of osteoid and widening of growth plate. Thus, continuous production of FGF23 reproduced clinical, biochemical, and histological features of TIO in vivo. Analyses for recombinant FGF23 products produced by Chinese hamster ovary cells indicated proteolytic cleavage of FGF23 at the RXXR motif. Recent genetic study indicates that missense mutations in this RXXR motif of FGF23 are responsible for autosomal dominant hypophosphatemic rickets, another hypophosphatemic disease with similar features to TIO. We conclude that overproduction of FGF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF23.

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Author and article information

Contributors

Signe Sparre Beck-Nielsen: sbeck-nielsen@dadlnet.dk

Zulf Mughal: Zulf.Mughal@mft.nhs.uk

Dieter Haffner: Haffner.Dieter@mh-hannover.de

Ola Nilsson: Ola.Nilsson@ki.se

Elena Levtchenko: elena.levtchenko@uzleuven.be

Gema Ariceta: gariceta@vhebron.net

Carmen de Lucas Collantes: mcdelucas@yahoo.es

Dirk Schnabel: Dirk.Schnabel@charite.de

Ravi Jandhyala:

ORCID: http://orcid.org/0000-0001-8504-6718

ravi@medialis.co.uk

Outi Mäkitie: outi.makitie@helsinki.fi

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 26 February 2019

Publication date PMC-release: 26 February 2019

Publication date Collection: 2019

Volume: 14

Electronic Location Identifier: 58

Affiliations

[1 ]ISNI 0000 0004 0512 597X, GRID grid.154185.c, Centre for Rare Diseases, , Aarhus University Hospital, ; Aarhus, Denmark

[2 ]ISNI 0000 0001 0235 2382, GRID grid.415910.8, Royal Manchester Children’s Hospital, ; Manchester, UK

[3 ]ISNI 0000 0000 9529 9877, GRID grid.10423.34, Hannover Medical School, ; Hannover, Germany

[4 ]ISNI 0000 0001 0738 8966, GRID grid.15895.30, Karolinska Institutet, Stockholm, Sweden and Örebro University, ; Örebro, Sweden

[5 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Katholieke Universiteit Leuven, ; Leuven, Belgium

[6 ]GRID grid.7080.f, Hospital Universitario Materno-Infantil Vall d’Hebron, , Universitat Autonoma de Barcelona, ; Barcelona, Spain

[7 ]ISNI 0000 0004 1767 5442, GRID grid.411107.2, Hospital Niño Jesús, ; Madrid, Spain

[8 ]University Children’s Hospital of Berlin, Berlin, Germany

[9 ]Medialis Ltd, Banbury, UK

[10 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Children’s Hospital, , University of Helsinki and Helsinki University Hospital, ; Helsinki, Finland

Author information

Ravi Jandhyala http://orcid.org/0000-0001-8504-6718

Article

Publisher ID: 1014

DOI: 10.1186/s13023-019-1014-8

PMC ID: 6390548

PubMed ID: 30808384

SO-VID: 82107c5e-3f24-4df6-93b7-500e80a01005

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 26 October 2018

Date accepted : 30 January 2019

Funding

Funded by: Kyowa Kirin Services Ltd

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: x-linked hypophosphatemia (xlh),fibroblast growth factor 23 (fgf23),phosphate regulating endopeptidase homolog, x-linked (phex),hypophosphatemia,vitamin d deficiency,rickets,osteomalacia,bone dysplasia,ectopic calcification,muscle weakness,dental abscess,hearing impairment

Data availability: