This review summarizes the current knowledge of fibroblast growth factor 23 signaling in bone and its role in the disease pathology of X-linked hypophosphatemia. Craniosynostosis is an under-recognized complication of X-linked hypophosphatemia. The clinical implications and potential cellular mechanisms invoked by increased fibroblast growth factor 23 signaling causing craniosynostosis are reviewed. Knowledge gaps are identified and provide direction for future clinical and basic science studies.
Beck-NielsenSSBrock-JacobsenBGramJBrixenKJensenTK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark.Eur J Endocrinol2009;160:491–7
2.
FrancisFHennigSKornBReinhardtRde JongPPoustkaALehrachHRowePSNGouldingJNSummerfieldTMountfordRReadAPPopowskaEPronickaEDaviesKEO’RiordanJLHEconsMJNesbittTDreznerMKOudetCPannetierSHanauerAStromTMMeindlALorenzBCagnoliBMohnikeKLMurkenJMeitingerT. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.Nat Genet1995;11:130–6
3.
BarrosNMHoacBNevesRLAddisonWNAssisDMMurshedMCarmonaAKMcKeeMD. Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia.J Bone Miner Res2013;28:688–99
4.
MuraliSKAndrukhovaOClinkenbeardELWhiteKEErbenRG. Excessive osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in Hyp mice.PLoS Biol2016;14:e1002427
5.
BeckLSoumounouYMartelJKrishnamurthyGGauthierCGoodyerCGTenenhouseHS. Pex/PEX tissue distribution and evidence for a deletion in the 3’ region of the Pex gene in X-linked hypophosphatemic mice.J Clin Invest1997;99:1200–9
6.
RuchonAFMarcinkiewiczMSiegfriedGTenenhouseHSDesGroseillersLCrinePBoileauG. Pex mRNA is localized in developing mouse osteoblasts and odontoblasts.J Histochem Cytochem1998;46:459–68
7.
WestbroekIDe RooijKENijweidePJ. Osteocyte-specific monoclonal antibody MAb OB7.3 is directed against Phex protein.J Bone Miner Res2002;17:845–53
8.
LiuSRowePSVierthalerLZhouJQuarlesLD. Phosphorylated acidic serine-aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity.J Endocrinol2007;192:261–7
9.
UrakawaIYamazakiYShimadaTIijimaKHasegawaHOkawaKFujitaTFukumotoSYamashitaT. Klotho converts canonical FGF receptor into a specific receptor for FGF23.Nature2006;444:770–4
10.
GattineniJBatesCTwombleyKDwarakanathVRobinsonMLGoetzRMohammadiMBaumM. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1.Am J Physiol Renal Physiol2009;297:F282–91
11.
CarpenterTOImelEAHolmIAJandeBeurSMInsognaKL. A clinician’s guide to X-linked hypophosphatemia.J Bone Miner Res2011;26:1381–8
12.
CurrarinoG. Sagittal synostosis in X-linked hypophosphatemic rickets and related diseases.Pediatr Radiol2007;37:805–12
13.
RothenbuhlerAFadelNDebzaYBacchettaJDialloMTAdamsbaumCLinglartADi RoccoF. High incidence of cranial synostosis and chiari I malformation in children with X-linked hypophosphatemic rickets (XLHR).J Bone Miner Res2019;34:490–96
14.
ShettyNSMeyerRAJr.Craniofacial abnormalities in mice with X-Linked hypophosphatemic genes (Hyp or Gy).Teratology1991;44:463–72
15.
Beck-NielsenSSMughalZHaffnerDNilssonOLevtchenkoEAricetaGDe Lucas CollantesCSchnabelDJandhyalaRMäkitieO. FGF23 and its role in X-linked hypophosphatemia-related morbidity.Orphanet J Rare Dis2019;14:1–25
16.
GoetzRNakadaYHuMCKurosuHWangLNakataniTShiMEliseenkovaAVRazzaqueMSMoeOWKuro-oMMohammadiM. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation.Proc Natl Acad Sci U S A2010;107:407–12
17.
TagliabracciVSEngelJLWileySEXiaoJGonzalezDJAppaiahHNKollerANizetVWhiteKEDixonJE. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis.Proc Natl Acad Sci U S A2014;111:5520–5
18.
ShimadaTMutoTUrakawaIYoneyaTYamazakiYOkawaKTakeuchiYFujitaTFukumotoSYamashitaT. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.Endocrinology2002;143:3179–82
19.
KatoKJeanneauCTarpMABenet-PagèsALorenz-DepiereuxBBennettEPMandelUStromTMClausenH. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation.J Biol Chem2006;281:18370–7
20.
TopazOShurmanDLBergmanRIndelmanMRatajczakPMizrachiMKhamaysiZBeharDPetroniusDFriedmanVZelikovicIRaimerSMetzkerARichardGSprecherE. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.Nat Genet2004;36:579–81
21.
LiuSGuoRSimpsonLGXiaoZ-SBurnhamCEQuarlesLD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX.J Biol Chem2003;278:37419–26
22.
ClinkenbeardELCassTANiPHumJMBellidoTAllenMRWhiteKE. Conditional deletion of murine Fgf23: interruption of the normal skeletal responses to phosphate challenge and rescue of genetic hypophosphatemia.J Bone Miner Res2016;31:1247–57
23.
SaitoHMaedaAOhtomoSIHirataMKusanoKKatoSOgataESegawaHMiyamotoKIFukushimaN. Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D 3 and phosphorus in vivo.J Biol Chem2005;280:2543–9
24.
ZhouWSimicPZhouIYCaravanPVela ParadaXWenDWashingtonOLShvedovaMPierceKAClishCBMannstadtMKobayashiTWeinMNJüppnerHRheeEP. Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis.J Clin Invest2023;133:e164610
25.
LarssonTMarsellRSchipaniEOhlssonCLjunggren TenenhouseÖHSJüppnerHJonssonKB. Transgenic mice expressing fibroblast growth factor 23 under the control of the α1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis.Endocrinology2004;145:3087–94
26.
ShimadaTHasegawaHYamazakiYMutoTHinoRTakeuchiYFujitaTNakaharaKFukumotoSYamashitaT. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res2004;19:429–35
27.
BaiXMiaoDXiaoSQiuDSt-ArnaudRPetkovichMGuptaAGoltzmanDKaraplisAC. CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders.J Clin Invest2016;126:667–80
28.
YoungKBeggsMRGrimblyCAlexanderRT. Regulation of 1 and 24 hydroxylation of vitamin D metabolites in the proximal tubule.Exp Biol Med2022;247:1103–11
29.
BergwitzCMiyamotoKI. Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy.Pflugers Arch2019;471:149–63
30.
KawaiM. The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis.Horm Mol Biol Clin Investig2016;28:55–67
31.
KinoshitaYFukumotoS. X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases: prospect for new treatment.Endocr Rev2018;39:274–91
32.
WaltonRJBijvoetOL. Nomogram for derivation of renal threshold phosphate concentration.Lancet1975;2:309–10
33.
AlonUHellersteinS. Assessment and interpretation of the tubular threshold for phosphate in infants and children.Pediatr Nephrol1994;8:250–1
34.
BrodehlJGellissenKWeberHP. Postnatal development of tubular phosphate reabsorption.Clin Nephrol1982;17:163–71
35.
StarkHEisensteinBTiederMRachmelAAlpertG. Direct measurement of TP/GFR: a simple and reliable parameter of renal phosphate handling.Nephron1986;44:125–8
36.
JonssonKBZahradnikRLarssonTWhiteKESugimotoTImanishiYYamamotoTHampsonGKoshiyamaHLjunggren ObaÖKYangIMMiyauchiAEconsMJLavigneJJüppnerH. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.N Engl J Med2003;348:1656–63
37.
Benet-PagèsALorenz-DepiereuxBZischkaHWhiteKEEconsMJStromTM. FGF23 is processed by proprotein convertases but not by PHEX.Bone2004;35:455–62
38.
RossFPChappelJAlvarezJISanderDButlerWTFarach-CarsonMCMintzKARobeyPGTeitelbaumSLChereshDA. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin α(v)β3 potentiate bone resorption.J Biol Chem1993;268:9901–7
39.
ReinholtFPHultenbyKOldbergAHeinegårdD. Osteopontin—A possible anchor of osteoclasts to bone.Proc Natl Acad Sci U S A1990;87:4473–5
40.
AddisonWNMasicaDLGrayJJMcKeeMD. Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage.J Bone Miner Res2010;25:695–705
41.
AddisonWNNakanoYLoiselTCrinePMcKeeMD. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM.J Bone Miner Res2008;23:1638–49
42.
RowePS. Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway.Crit Rev Eukaryot Gene Expr2012;22:61–86
43.
MariePJGlorieuxFH. Relation between hypomineralized periosteocytic lesions and bone mineralization in vitamin D-resistant rickets.Calcif Tissue Int1983;35:443–8
44.
XiaoZSCrenshawMGuoRNesbittTDreznerMKQuarlesLD. Intrinsic mineralization defect in Hyp mouse osteoblasts.Am J Physiol1998;275:E700–8
45.
BreslerDBruderJMohnikeKFraserWDRowePS. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets.J Endocrinol2004;183:R1–9
VegaRAOpalakCHarshbargerRJFearonJARitterAMCollinsJJRhodesJL. Hypophosphatemic rickets and craniosynostosis: a multicenter case series.J Neurosurg Pediatr2016;17:694–700
48.
VakhariaJDMatlockKTaylorHOBackeljauwPFToporLS. Craniosynostosis as the presenting feature of X-linked hypophosphatemic rickets.Pediatrics2018;141:S515–9
49.
HolmIANelsonAERobinsonBGMasonRSMarshDJCowellCTCarpenterTO. Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked2006;86:3889–99
50.
ParkPGLimSHLeeHKAhnYHCheongHIlKangHG. Genotype and phenotype analysis in X-linked hypophosphatemia.Front Pediatr2021;9:699767
51.
JaszczukPRogersGFGuzmanRProctorMR. X-linked hypophosphatemic rickets and sagittal craniosynostosis: three patients requiring operative cranial expansion: case series and literature review.Child’s Nerv Syst2016;32:887–91
52.
GlassLRDagiTFDagiLR. Papilledema in the setting of X-linked hypophosphatemic rickets with craniosynostosis.Case Rep Ophthalmol2011;2:376–81
53.
WillisFRBeattieTJ. Craniosynostosis in X-linked hypophosphataemic rickets.J Paediatr Child Health1997;33:78–9
54.
WattsLWordsworthP. Chiari malformation, syringomyelia and bulbar palsy in X linked hypophosphataemia.BMJ Case Rep2015;2015:bcr2015211961
55.
FreudlspergerCHoffmannJCastrillon-OberndorferGEngelM. Bilateral coronal and sagittal synostosis in X-linked hypophosphatemic rickets: a case report.J Craniomaxillofac Surg2013;41:842–4
56.
ChesherDOddyMDarbarUSayalPCaseyARyanASechiASimisterCWatersAWedatilakeYLachmannRHMurphyE. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations.J Inherit Metab Dis2018;41:865–76
57.
ShanbhogueVVHansenSFolkestadLBrixenKBeck-NielsenSS. Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in adult patients with hypophosphatemic rickets.J Bone Miner Res2015;30:176–83
58.
GjørupHKjaerIBeck-NielsenSSPoulsenMRHaubekD. A radiological study on intra- and extra-cranial calcifications in adults with X-linked hypophosphatemia and associations with other mineralizing enthesopathies and childhood medical treatment.Orthod Craniofac Res2016;19:114–25
59.
RauchF. Material matters: a mechanostat-based perspective on bone development in osteogenesis imperfecta and hypophosphatemic rickets.J Musculoskelet Neuronal Interact2006;6:142–6
60.
WilkieAO. Craniosynostosis: genes and mechanisms.Hum Mol Genet1997;6:1647–56
61.
MostafaYAEl-MangouryNHMeyerRAJrIorioRJ. Deficient nasal bone growth in the X-linked hypophosphataemic (HYP) mouse and its implication in craniofacial growth.Arch Oral Biol1982;27:311–7
62.
RoyWAIorioRJMeyerGA. Craniosynostosis in vitamin D-resistant rickets. A mouse model.J Neurosurg1981;55:265–71
63.
IorioRJMurrayGMeyerRAJr.Craniometric measurements of craniofacial malformations in mice with X-linked, dominant hypophosphatemia (vitamin D-resistant rickets).Teratology1980;22:291–8
64.
MurthyAS. X-linked hypophosphatemic rickets and craniosynostosis.J Craniofac Surg2009;20:439–42
65.
MiyagawaKYamazakiMKawaiMNishinoJKoshimizuTOhataYTachikawaKMikuni-TakagakiYKogoMOzonoKMichigamiT. Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice.PLoS ONE2014;9:e93840
66.
XiaoZHuangJCaoLLiangYHanXQuarlesLD. Osteocyte-specific deletion of Fgfr1 suppresses FGF23.PLoS ONE2014;9:e104154
67.
HessleLJohnsonKAAndersonHCNarisawaSSaliAGodingJWTerkeltaubRMillánJL. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization.Proc Natl Acad Sci U S A2002;99:9445–9
68.
NamHKEmmanouilEHatchNE. Deletion of the pyrophosphate generating enzyme ENPP1 rescues craniofacial abnormalities in the TNAP-/- mouse model of hypophosphatasia and reveals FGF23 as a marker of phenotype severity.Front Dent Med2022;3:846962
69.
WhyteMP. Hypophosphatasia-aetiology, nosology, pathogenesis, diagnosis and treatment.Nat Rev Endocrinol2016;12:233–46
70.
VogtMGirschickHSchweitzerTBenoitCHoll-WiedenASeefriedLJakobFHofmannC. Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children.Orphanet J Rare Dis2020;15:212
71.
CollmannHMornetEGattenlöhnerSBeckCGirschickH. Neurosurgical aspects of childhood hypophosphatasia.Childs Nerv Syst2009;25:217–23
72.
LiuJNamHKWangEHatchNE. Further analysis of the crouzon mouse: effects of the FGFR2C342Y mutation are cranial bone-dependent.Calcif Tissue Int2013;92:451–66
73.
WangENamHKLiuJHatchNE. The effects of tissue-non-specific alkaline phosphatase gene therapy on craniosynostosis and craniofacial morphology in the FGFR2C342Y/+ mouse model of Crouzon craniosynostosis.Orthod Craniofac Res2015;18:196–206
74.
LiangGKatzLDInsognaKLCarpenterTOMacicaCM. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice.Calcif Tissue Int2009;85:235–46
75.
SchlessingerJPlotnikovANIbrahimiOAEliseenkovaAVYehBKYayonALinhardtRJMohammadiM. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.Mol Cell2000;6:743–50
76.
ChenGLiuYGoetzRFuLJayaramanSHuMCMoeOWLiangGLiXMohammadiM. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.Nature2018;553:461–6
77.
ReillyBJLeemingJMFraserD. Craniosynostosis in the rachitic spectrum.J Pediatr1964;64:396–405
78.
MacicaCMLuoJTommasiniSM. The enthesopathy of XLH is a mechanical adaptation to osteomalacia: biomechanical evidence from Hyp mice.Calcif Tissue Int2022;111:313–22
