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FGF23 and Its Role in X-Linked Hypophosphatemia-Related Morbidity

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FGF23 and Its Role in X-Linked Hypophosphatemia-Related Morbidity Beck-Nielsen et al. Orphanet Journal of Rare Diseases (2019) 14:58 https://doi.org/10.1186/s13023-019-1014-8 REVIEW Open Access FGF23 and its role in X-linked hypophosphatemia-related morbidity Signe Sparre Beck-Nielsen1, Zulf Mughal2, Dieter Haffner3, Ola Nilsson4, Elena Levtchenko5, Gema Ariceta6, Carmen de Lucas Collantes7, Dirk Schnabel8, Ravi Jandhyala9* and Outi Mäkitie10 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), fibroblast growth factor 23 (FGF23), phosphate regulating endopeptidase homolog, X-linked (PHEX), hypophosphatemia, vitamin D deficiency, rickets, osteomalacia,bonedysplasia,ectopic calcification, muscle weakness, dental abscess, hearing impairment Background and Introduction depicted in Fig. 1, and include impaired growth, rickets, X-linked hypophosphatemia (also known as X-linked osteomalacia, bone abnormalities, bone pain, spontan- hypophosphatemic rickets, XLH; OMIM: #307800) is eous dental abscesses, hearing difficulties, enthesopa- an inherited disease of phosphate metabolism, where thy, osteoarthritis, and muscular dysfunction [2, 3]. inactivating mutations of the Phosphate Regulating PHEX is predominantly expressed in osteoblasts and Endopeptidase Homolog, X-Linked (PHEX,OMIM: codes for an enzyme that degrades local small #300550) gene lead to local and systemic effects. XLH integrin-binding ligand, N-linked glycoproteins (SIBLING affects approximately 1:20,000 individuals [1]whoex- proteins), particularly osteopontin (OPN) [4], and sup- perience a diverse range of medical problems that are presses serum levels of the phosphatonin, fibroblast growth factor 23 (FGF23). Despite being an enzyme, PHEX is * Correspondence: [email protected] thought to affect expression [5] rather than degradation of 9Medialis Ltd, Banbury, UK FGF23 [6, 7]. Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This 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. Beck-Nielsen et al. Orphanet Journal of Rare Diseases (2019) 14:58 Page 2 of 25 Fig. 1 Symptomatology and pathophysiology of XLH. The signs, symptoms, sequelae, and long-term consequences of XLH in paediatric (left) and adult (right) patients Downregulation of PHEX in XLH increases skeletal Although hypophosphatemia is the primary link be- OPN deposition which contributes to local inhibition of tween elevated FGF23 and the pathophysiology of XLH, mineralisation [4]. Meanwhile, elevated levels of serum FGF23 has recently been proposed to also contribute to FGF23 increase urinary phosphate excretion by down- XLH via other molecular mechanisms [7, 15]. regulating renal sodium-phosphate transporters, and This review describes the central role of FGF23 in limit intestinal phosphate absorption by restricting active XLH pathophysiology, outlining evidence that links vitamin D synthesis to levels that are abnormally low or upregulation of FGF23 to manifestations of XLH normal despite hypophosphatemia [8]. through various molecular pathways (outlined in Fig. 2). Since phosphate insufficiency and inappropriately FGF23 is introduced along with its direct regulators and low levels of calcitriol [also known as 1,25(OH)2Dor receptors, followed by a brief discussion of the dysregu- active vitamin D] contribute to many symptoms of lation of serum FGF23 in various diseases of hypopho- XLH, conventional therapy involves supplementation sphatemia; animal models of these diseases are also with oral phosphate and calcitriol or calcitriol ana- described since they are essential for understanding mo- logues (commonly alfacalcidol). This can correct lower lecular mechanisms involved in the pathology of XLH. limb deformities, promote growth, and improve oral Finally, the manifestations of XLH are grouped by mo- health [9], with earlier treatment leading to better lecular mechanism and discussed, with any potential in- results [10]. However, conventional therapy insuffi- volvement of FGF23 highlighted. ciently corrects the biochemistry and symptoms of XLH, and can further increase serum FGF23 levels Regulation of serum FGF23 [8, 11–13]. Conventional therapy has also been asso- The FGF23 gene is located on chromosome 12 and codes ciated with adverse effects including secondary for a 251-amino acid, 32 kDa pro-protein. Although hyperparathyroidism, nephrocalcinosis, nephrolithia- FGF23 is predominantly expressed in and secreted by os- sis, and cardiovascular abnormalities [14]. teocytes and osteoblasts, lower levels of FGF23 expression Beck-Nielsen et al. Orphanet Journal of Rare Diseases (2019) 14:58 Page 3 of 25 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 have been detected in rodents in many non-bone tissues, secretion, and the resulting C- and N-terminal frag- including teeth and brain [16–18]. ments are then released from the cell along with the A 24-amino acid signalling peptide is cleaved from remaining active FGF23; these FGF23 fragments are FGF23 post-translationally and directs active FGF23 not thought to have any innate biological activity [19, protein (227 amino acids) to the Golgi apparatus for 20] . FGF23 can either act locally or enter the blood- secretion. Some active FGF23 is further cleaved during stream to interact with distant cell surface receptors. Beck-Nielsen et al. Orphanet Journal of Rare Diseases (2019) 14:58 Page 4 of 25 The molecular pathways involved in regulation of these is encoded by the GALNT3 gene [35, 36]. Homozygous processes are complex, and therefore are only briefly inactivating mutations in GALNT3 result in low levels of depicted in Fig. 2 and summarised below. intact FGF23 and familial tumoral calcinosis syndrome, a condition characterised by hyperphosphatemia and Factors that regulate FGF23 expression extraskeletal calcifications [37]. There is also evidence Expression of FGF23 is predominantly regulated by that O-glycosylation can be blocked by FAM20C-medi- serum phosphate and calcitriol [21]. Phosphate-induced ated phosphorylation [19], and that FGF23 can be elevation of serum FGF23 mostly occurs in bone [22]. cleaved by proprotein convertases [38], although these The nature of this “phosphate sensing” mechanism is yet findings have been challenged [34]. to be fully elucidated, but has been proposed to involve A recent study found that both expression and cleav- nicotinamide adenine dinucleotide phosphate (NAD- age of FGF23 was promoted by iron deficiency and PH)-induced production of reactive oxygen species inflammation, so that secretion of C-terminal fragments (ROS), and the mitogen-activated protein kinase was upregulated without significantly affecting serum kinase-extracellular signal-regulated kinases (MEK- concentrations of
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