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

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.

Keywords: X-linked hypophosphatemia (XLH); bone dysplasia; dental abscess; ectopic calcification; fibroblast growth factor 23 (FGF23); hearing impairment; hypophosphatemia; muscle weakness; osteomalacia; phosphate regulating endopeptidase homolog, X-linked (PHEX); rickets; vitamin D deficiency.

Fig. 1

Symptomatology and pathophysiology of XLH. The signs, symptoms, sequelae, and long-term consequences of XLH in paediatric (left) and adult (right) patients

Fig. 2

Regulation of FGF23 expression and secretion in XLH. Inactivating mutations in PHEX increase fibroblast growth factor 23 (FGF23) expression by increasing levels of acidic serine aspartate-rich-MEPE-associated protein (ASARM) peptide. This leads to increased release of FGF23 into the serum, and increased levels of FGF23-mediated signalling. These processes are also regulated by a wide range of other mechanisms. Green lines indicate upregulation and red lines indicate repression. For simplification, feedback loops have been represented as linear pathways centred around FGF23

Fig. 3

FGF23-receptor interactions. Schematic diagram of known and potential interactions between FGF23 (green circle) and its various receptors (blue and yellow). (left) FGF23 is known to bind in a KLOTHO (red)-dependent fashion to FGFRs 1, 2, and 3, (centre) and to bind to FGFR4 independently of KLOTHO. (right) KLOTHO-independent interactions with other receptors have also been proposed

Fig. 4

Mutation analysis of human PHEX. Mutations that span multiple exons (top section) are represented by lines, while intron-specific (middle section) and exon-specific (lower section) mutations are clustered by loci. Affected nucleotides are numbered. A, adenine; C, cytosine; G, guanine; T, thymine; del, deletion mutations; dup, duplication mutations; ins, insertion mutations; delins, combination deletion/insertion mutations; >, substitution mutations [56]

Fig. 5

FGF23 and bone abnormalities. Schematic illustrations of (a) hypophosphatemic and (b) autocrine/paracrine molecular pathways that have been proposed to link FGF23 to bone abnormalities in XLH

Fig. 6

FGF23 and kidney abnormalities. Elevated levels of FGF23 in XLH increase renal expression of TRPV5 calcium channels, contributing to local excesses of calcium and general hypercalcemia, which may contribute to enthesopathies and calcification of arteries, resulting in hypertension and cardiovascular disease. Although nephrocalcinosis occurs in XLH as a side-effect of conventional therapy, the TRPV5-mediated increase in renal calcium absorption may play a permissive role

Fig. 7

FGF23 and cranial abnormalities. Over-expression of FGF23 leads to up-regulation of FGFR2/3 signalling. Cross-binding of FGF23 with FGFR2/3 at cranial sutures, impaired endochondral ossification of the skull, and osteomalacia-induced malformation of the base plate can all lead to craniosynostosis

Fig. 8

FGF23 and dental abnormalities. A schematic representation of molecular pathways that have been proposed to contribute to dental manifestations of XLH

Fig. 9

Mechanisms of hearing loss in XLH. A schematic illustration of the structure of the ear is overlaid with the molecular pathways that may connect FGF23 to hearing loss in XLH