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Frontiers of Medicine

Front Med    2013, Vol. 7 Issue (1) : 65-80     DOI: 10.1007/s11684-013-0254-6
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FGF23 associated bone diseases
Eryuan Liao()
Institute of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha 410011, China
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Abstract

Recently, fibroblast growth factor 23 (FGF23) has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism. In this review, we summarized the FGF superfamily, the mechanism of FGF23 on phosphate and vitamin D metabolism, and the FGF23 related bone disease.

Keywords fibroblast growth factor 23      FGF receptor      phosphate metabolism      Klotho      bone disease     
Corresponding Authors: Liao Eryuan,Email:eyliao007@yahoo.com.cn   
Issue Date: 05 March 2013
 Cite this article:   
Eryuan Liao. FGF23 associated bone diseases[J]. Front Med, 2013, 7(1): 65-80.
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http://journal.hep.com.cn/fmd/EN/10.1007/s11684-013-0254-6
http://journal.hep.com.cn/fmd/EN/Y2013/V7/I1/65
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Fig.1  FGF superfamily. FGF13 is an FGF family member. FGF4-like members result from multiplex gene expression of FGF13, which is also an important FGF. FGF15 and 19 are hormone-like FGFs produced by transformation of the genes of FGF4-like members.
Fig.1  FGF superfamily. FGF13 is an FGF family member. FGF4-like members result from multiplex gene expression of FGF13, which is also an important FGF. FGF15 and 19 are hormone-like FGFs produced by transformation of the genes of FGF4-like members.
GenePathogenesisDiseaseFGF signal
Hereditary diseases
FGF23Activating mutationADHR
PHEXInactivating mutationXLH
DMP1Inactivating mutationARHR
FGF23/GalntInactivating mutationFTC
Paraneoplastic syndrome
FGF19Excessive secretionExtrahepatic cholestasis
FGF23Excessive secretionTIO
Metabolic disease
FGF19?Chronic hemolysis
FGF19?NAFLD
FGF21?T2DM
FGF21?Obesity
FGF21?Cushing’s syndrome
FGF21?Anorexia nervosa
FGF23?Renal failure
Tab.1  Diseases related to hormone-like FGFs
Fig.2  Regulatory pathway of FGF23. Solid lines represent promotion and dotted lines represent inhibition. Calcium, phosphorus and 1,25-(OH)D in food and serum can stimulate the synthesis of FGF23. Meanwhile, FGF23 directly inhibits the secretion of 1,25-(OH)D, and inhibits PTH and blocks the synthesis of 1,25-(OH)D. In contrast, FGF23 inhibits the reabsorption of phosphorus in the renal tubules to decrease serum phosphate levels, whereas hypophosphatemia stimulates secretion of 1,25-(OH)D. As a result, the serum level of 1,25-(OH)D depends on both FGF23 and the blood phosphate level. In patients with XLH, despite hypophosphatemia, serum 1,25-(OH)D remains in the low or normal range, so the inhibition by FGF23 of 1,25-(OH)D remains obvious. FGF23 has a similar influence on PTH.
Fig.2  Regulatory pathway of FGF23. Solid lines represent promotion and dotted lines represent inhibition. Calcium, phosphorus and 1,25-(OH)D in food and serum can stimulate the synthesis of FGF23. Meanwhile, FGF23 directly inhibits the secretion of 1,25-(OH)D, and inhibits PTH and blocks the synthesis of 1,25-(OH)D. In contrast, FGF23 inhibits the reabsorption of phosphorus in the renal tubules to decrease serum phosphate levels, whereas hypophosphatemia stimulates secretion of 1,25-(OH)D. As a result, the serum level of 1,25-(OH)D depends on both FGF23 and the blood phosphate level. In patients with XLH, despite hypophosphatemia, serum 1,25-(OH)D remains in the low or normal range, so the inhibition by FGF23 of 1,25-(OH)D remains obvious. FGF23 has a similar influence on PTH.
Fig.3  Interaction of FGF23 and PHEX, and their influence on serum 1,25-(OH)D and phosphate levels. FGF23 secreted from osteocytes binds to FGFR1, and inhibits the NaPi symporter and the activity of 1α-hydroxylase (CTP27B1). PHEX from osteoblasts activates inactive factor (Fi) to produce active factor (Fa), which exists upstream of FGF23. Fa inactivates FGF23. Elevation of 1,25-(OH)D inhibits PHEX activity through a negative feedback pathway. Fa levels in patients with XLH are decreased due to a loss-of-function mutation. This can result in increased levels of FGF23, consumption of phosphorus and an “inappropriate” decrease of 1,25-(OH)D.
Fig.3  Interaction of FGF23 and PHEX, and their influence on serum 1,25-(OH)D and phosphate levels. FGF23 secreted from osteocytes binds to FGFR1, and inhibits the NaPi symporter and the activity of 1α-hydroxylase (CTP27B1). PHEX from osteoblasts activates inactive factor (Fi) to produce active factor (Fa), which exists upstream of FGF23. Fa inactivates FGF23. Elevation of 1,25-(OH)D inhibits PHEX activity through a negative feedback pathway. Fa levels in patients with XLH are decreased due to a loss-of-function mutation. This can result in increased levels of FGF23, consumption of phosphorus and an “inappropriate” decrease of 1,25-(OH)D.
Fig.4  Signal transduction system of FGF23 in the proximal tubule. FGF23 in the renal proximal tubule binds to the FGFR1α-Klotho complex, activates ERK1/2 kinase and causes phosphorylation of SGK1. Phosphorylated SGK1 phosphorylates NHERF-1 and internalizes and degrades NaPi-2a. PTH activates PKA and PKC, which also phosphorylate NHERF-1.
Fig.4  Signal transduction system of FGF23 in the proximal tubule. FGF23 in the renal proximal tubule binds to the FGFR1α-Klotho complex, activates ERK1/2 kinase and causes phosphorylation of SGK1. Phosphorylated SGK1 phosphorylates NHERF-1 and internalizes and degrades NaPi-2a. PTH activates PKA and PKC, which also phosphorylate NHERF-1.
Wild type miceFGF23 deficient mice (FGF23 knockout model)Mice secreting high levels of FGF23 (XLH model)
BSP expressionNo cells or extracellular matrix in dentinSignificantly increased extracellular matrixSimilar to wild type mice, but no thickening of dentine
DMP1 expressionOsteocytes; lacunae surrounding boneNo thickening of dentine; increased bone and extracellular matrixIncreased extracellular matrix
DSP expressionLocated in dentin canal and mantle dentinMassively located in dentin canal and mantle dentinNot expressed in dentin canal; seldom expressed in mantle dentin
DPP expressionOdontoblasts; mineralization front of dentin and predentin; mantle dentinIncreased mantle dentin; weakly expressed in odontoblasts; weakly expressed in mineralization front of dentin and predentinNormally expressed in odontoblasts; weakly expressed in mantle dentin; not expressed in mineralization front of dentin and predentin
Tab.2  Effect of FGF23 on the SIBLINGs family
Fig.5  Relationship between absence of Klotho with progression of nephropathy and vascular calcification. Under physiological conditions, Klotho is a key protective factor against vessel injury and calcification. The mechanisms involved include the following. (1) Absence of Klotho injures the kidney, and urinary phosphorus is increased to prevent hyperphosphatemia. (2) When Klotho is absent, normal serum phosphorus levels cannot be maintained, which results in hyperphosphouria. (3) Absence of Klotho attenuates the effect of the inhibition of the phosphonate entering the vascular smooth muscle and the dedifferentiation of cells, leading to vascular calcification and hypertension. (4) Hyperphosphatemia and high urine phosphorus stimulate the secretion of PTH and increase the calcium × phosphorus product in urine and blood, leading to vascular calcification and renal hypertension.
Fig.5  Relationship between absence of Klotho with progression of nephropathy and vascular calcification. Under physiological conditions, Klotho is a key protective factor against vessel injury and calcification. The mechanisms involved include the following. (1) Absence of Klotho injures the kidney, and urinary phosphorus is increased to prevent hyperphosphatemia. (2) When Klotho is absent, normal serum phosphorus levels cannot be maintained, which results in hyperphosphouria. (3) Absence of Klotho attenuates the effect of the inhibition of the phosphonate entering the vascular smooth muscle and the dedifferentiation of cells, leading to vascular calcification and hypertension. (4) Hyperphosphatemia and high urine phosphorus stimulate the secretion of PTH and increase the calcium × phosphorus product in urine and blood, leading to vascular calcification and renal hypertension.
Fig.6  Ca-1,25-(OH)D-FGF23 system of phosphorus metabolism. Vitamin D and calcium inhibit the secretion of PTH through the vitamin D receptor and calcium receptor. Through the interaction of FGF23 with Klotho, PTH is inhibited. Other factors can also inhibit the secretion of PTH, such as the calcium sensing receptor and the calcium receptor. The mechanism by which FGF23 inhibits the secretion of PTH from the parathyroids is unclear. With the assistance of FGF23, membrane-bound Klotho can inhibit PTH, but this needs further investigation.
Fig.6  Ca-1,25-(OH)D-FGF23 system of phosphorus metabolism. Vitamin D and calcium inhibit the secretion of PTH through the vitamin D receptor and calcium receptor. Through the interaction of FGF23 with Klotho, PTH is inhibited. Other factors can also inhibit the secretion of PTH, such as the calcium sensing receptor and the calcium receptor. The mechanism by which FGF23 inhibits the secretion of PTH from the parathyroids is unclear. With the assistance of FGF23, membrane-bound Klotho can inhibit PTH, but this needs further investigation.
Fig.7  Regulation of phosphorus by the PTH-1,25-(OH)D-FGF23 system. Solid lines show promotion and dotted lines show inhibition.
Fig.7  Regulation of phosphorus by the PTH-1,25-(OH)D-FGF23 system. Solid lines show promotion and dotted lines show inhibition.
Fig.8  Interaction and relationship between FGF23, PTH, 1,25-(OH)D and Klotho. (A) The PTH-1,25-(OH)D axis primarily regulates the metabolism of calcium and the balance of serum calcium. PTH secreted from the parathyroids increases when serum calcium is decreased and decreases the excretion of calcium in the urine; it also activates 1α-hydroxylase, increasing the excretion of phosphate. PTH increases the release of calcium and phosphorus from bone, and 1,25-(OH)D increases the absorption of calcium and phosphorus in the intestine and inhibits the secretion of PTH. (B) FGF23-Klotho axis. FGF23 produced by osteocytes increases the excretion of phosphorus from the kidney and decreases the serum phosphorus level. 1,25-(OH)D decreases the excretion of phosphate and the activity of 1α-hydroxylase.
Fig.8  Interaction and relationship between FGF23, PTH, 1,25-(OH)D and Klotho. (A) The PTH-1,25-(OH)D axis primarily regulates the metabolism of calcium and the balance of serum calcium. PTH secreted from the parathyroids increases when serum calcium is decreased and decreases the excretion of calcium in the urine; it also activates 1α-hydroxylase, increasing the excretion of phosphate. PTH increases the release of calcium and phosphorus from bone, and 1,25-(OH)D increases the absorption of calcium and phosphorus in the intestine and inhibits the secretion of PTH. (B) FGF23-Klotho axis. FGF23 produced by osteocytes increases the excretion of phosphorus from the kidney and decreases the serum phosphorus level. 1,25-(OH)D decreases the excretion of phosphate and the activity of 1α-hydroxylase.
High FGF23 syndromeLow FGF23 syndrome
Primary high FGF23 syndrome(FGF23 increased, 1,25-(OH)2D “inappropriately”decreased)Primary low FGF23 syndrome(FGF23 decreased/activity decreased, 1,25-(OH)2D increased)
?ADHR ?Tumoral calcinosis
?TIO ?FGF23 inactive
?XLHSecondary low serum FGF23(FGF23 decreased, serum phosphate normal
?ARHRor decreased, 1,25-(OH)2D increased)
?FD ?Low phosphate diet
?After chalybeate injection through veins ?Vitamin D receptor mutation
Secondary high serum FGF23(serum phosphate normal or increased, ?1α-hydroxylase mutation
1,25-(OH)2D decreased) ?NaPi-2a deficiency/mutation
?Chronic nephrosis ?NaPi-2c mutation (HHRH)
?High phosphate diet
?Klotho deficiency disease
Tab.3  Diseases and clinical states that cause primary and secondary increases and decreases of FGF23
Fig.9  Pathogenesis and pathophysiology of hypophosphatemia. TIO: tumor-induced osteomalacia; XLH: X-linked hypophosphatemia; ARHR: autosomal recessive hypophosphatemic rickets; ADHR: autosomal dominant hypophosphatemic rickets; NPT2: type 2 sodium-phosphate cotransporter.
Fig.9  Pathogenesis and pathophysiology of hypophosphatemia. TIO: tumor-induced osteomalacia; XLH: X-linked hypophosphatemia; ARHR: autosomal recessive hypophosphatemic rickets; ADHR: autosomal dominant hypophosphatemic rickets; NPT2: type 2 sodium-phosphate cotransporter.
OMIMGeneMutationPathophysiologyPi1,25-(OH)2DFGF23C-terminal FGF23
ADHR193100FGF23: 605380)FGF23ActiveStability of FGF2 molecule ↑??/↑?/↑
XLH307800(PHEX: 300550)PHEXInactiveOsteocyteFGF23 synthesis↑?/↓?/↑?/↑
ARHR241520(DMP1: 600980)DMP1InactiveOsteocyteFGF23 synthesis↑??/↑?/↑
MAS/FD174800GNAS1ActiveLesionFGF23 synthesis ↑?? /↑?/↑
TIO605380(FGF23)TumorFGF23 synthesis ↑?/↓? / ↑?/↑
TC211900FGF23InactiveStability of FGF2 molecule↓?/↑
TC211900(GALNT3: 601756)GALNT3InactiveStability of FGF2 molecule↓?/↑
HHS610233GALNT3InactiveStability of FGF2 molecule↓?/↑
TC211900(KL604824)KLInactiveStability of FGF2 molecule↓?/↑
Tab.4  FGF23 associated hypophosphatemia
PatientMotherFatherNormal control
Gene typeR182W/S192LR182WS192L2.4–4.7
Serum phosphate(mg/dl)3.73.63.28.6–10.4
Serum calcium(mg/dl)9.99.69.742–128
ALP(U/L)581–76510871
Urinary calcium(mg)235249353Male<250Female<200
Urinary Ca/Cr(mg/mg)0.460.230.20<0.18
TRP1(%)838384>80
TmP/GFR1(μmol/ml)0.790.81–1.10
25-(OH)D(ng/ml)20413520–100
1,25-(OH)2D(pg/ml)377615920–71
Tab.5  Mineral metabolic characteristics of mutated NaPi-2c
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