Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism
© T. Saito and S. Fukumoto. 2009
Received: 28 May 2009
Accepted: 27 July 2009
Published: 22 September 2009
Derangements in serum phosphate level result in rickets/osteomalacia or ectopic calcification indicating that healthy people without these abnormalities maintain serum phosphate within certain ranges. These results indicate that there must be a regulatory mechanism of serum phosphate level. Fibroblast growth factor 23 (FGF23) was identified as the last member of FGF family. FGF23 is produced by bone and reduces serum phosphate level by suppressing phosphate reabsorption in proximal tubules and intestinal phosphate absorption through lowering 1,25-dihydroxyvitamin D level. It has been shown that excess and deficient actions of FGF23 result in hypophosphatemic rickets/osteomalacia and hyperphosphatemic tumoral calcinosis, respectively. These results indicate that FGF23 works as a hormone, and several disorders of phosphate metabolism can be viewed as endocrine diseases. It may become possible to treat patients with abnormal phosphate metabolism by pharmacologically modifying the activity of FGF23.
It is well known that serum calcium (Ca) level is regulated within a narrow range by actions of two calcium-regulating hormones, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. In contrast, while derangements in serum phosphate level result in rickets/osteomalacia or ectopic calcification, the regulatory mechanisms of serum phosphate have been largely unknown. Because PTH and 1,25(OH)2D can affect serum phosphate level, it has been unclear whether there is a tight mechanism of serum phosphate level regulated by a specific phosphate-regulating hormone. However, the identification of fibroblast growth factor 23 (FGF23) and subsequent studies certainly changed this view. FGF23 works as a phosphate-regulating hormone and aberrant functions of FGF23 result in several diseases. Here, we briefly review the physiological and pathophysiological roles of FGF23.
2. Structure and Function of FGF23
While it is well known that PTH also decreases serum phosphate level by reducing the expression of type 2a and 2c sodium-phosphate cotransporters, effects of FGF23 on serum phosphate can be observed in thyroparathyroidectomized rats . Therefore, while both PTH and FGF23 reduce the expression of sodium-phosphate cotransporters, FGF23 does not require PTH for its activity to reduce the expression of sodium-phosphate cotransporters. Although full-length FGF23 can induce hypophosphatemia, cleaved N-terminal and C-terminal fragments do not reduce serum phosphate level when injected into mice . Therefore, only the full-length FGF23 has the biological activity to reduce serum phosphate level.
3. FGF23 and Klotho
4. FGF23-Related Diseases
4.1. Hypophosphatemic Diseases
Causes of rickets/osteomalacia.
Autosomal dominant hypophosphatemic rickets/osteomalacia
(mutations in FGF23 gene)
Autosomal recessive hypophosphatemic rickets/osteomalacia
(mutations in DMP1 gene)
X-linked hypophosphatemic rickets/osteomalacia
(mutations in PHEX gene)
McCune-Albright syndrome/Fibrous dysplasia
(somatic mutations in GNAS1 gene)
Deficient action of 1,25(OH)2D
Vitamin D-dependent rickets type 1
(mutations in CYP27B1 gene)
Vitamin D-dependent rickets type 2 (mutations in VDR gene)
Dysfunction of renal tubules
Dent disease (mutations in CLCN5 gene)
Some renal tubular acidosis
Hereditary hypophosphatemic rickets/osteomalacia with hypercalcemia
(mutations in SLC34A3 gene)
Hypophosphatasia (mutations in TNALP gene)
Tumor-induced hypophosphatemic rickets/osteomalacia
Deficiency of vitamin D or phosphate
Vitamin D deficiency, shortage of daylight
Antiepileptic drugs, Saccharated ferric oxide (Iron polymaltose), Aluminum, and so forth
Chronic renal disease, and so forth
ADHR is a rare familial hypophosphatemic rickets/osteomalacia which does not respond to physiological dose of native vitamin D. FGF23 was identified as a responsible gene for ADHR by positional cloning in 2000 . Three heterozygous missense mutations around the processing site of FGF23 protein have been identified in ADHR families. These mutations replace 176Arg or 179Arg in FGF23 protein with other amino acids destroying R-X-X-R motif. Therefore, it has been presumed that the cleavage of FGF23 protein between 179Arg and 180Ser is prevented by these mutations causing increased full-length FGF23 level. However, the circulatory FGF23 levels in 42 ADHR patients were not significantly different from those of controls . On the other hand, FGF23 levels in ADHR patients fluctuate with time and are high when they show hypophosphatemia. These results indicate that FGF23 levels are not always high in patients with ADHR indicating that the resistance to the processing of FGF23 protein alone does not explain enhanced activity of FGF23 in these patients. We have previously shown that FGF23 levels are low in hypophosphatemic patients caused by other etiologies than FGF23 excess such as Fanconi syndrome and vitamin D deficiency . Therefore, high FGF23 levels in the presence of hypophosphatemia in patients with ADHR rather suggest that the regulatory mechanisms of FGF23 production are somehow deranged in these patients. Further studies are necessary to clarify the pathogenesis of hypophosphatemia in ADHR patients.
ARHR is also a rare familial hypophosphatemic rickets/osteomalacia which shows resistance to native vitamin D like ADHR. Almost all cases are observed in families with consanguineous marriage. Dentin matrix protein (DMP)1 was identified as a responsible gene for ARHR by positional cloning in 2006, and several homozygous mutations in DMP1 gene were identified in patients with ARHR [23, 24]. DMP1 is a matrix protein found in osteocytes and odontoblasts and belongs to a family of small integrin-binding ligand, N-linked glycoproteins (SIBLING) together with matrix proteins in calcified tissues such as dentin sialophosphoprotein (DSPP), integrin-binding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein (MEPE), and osteopontin. It is reported that homozygous DMP1 knock-out mice show features of hypophosphatemic rickets, and serum FGF23 levels of DMP1 knock-out mice and ARHR patients are high [23, 24]. In addition, FGF23 was shown to be abundantly expressed in osteocytes of DMP1-null mice. Therefore, excess production of FGF23 in osteocytes seems to cause ARHR. However, it remains unclear how mutations in DMP1 gene cause enhanced production of FGF23.
XLH is considered to be the most frequent cause of vitamin D-resistant hypophosphatemic rickets/osteomalacia. The frequency of XLH is reported to be about 1 in 20 000 births . The responsible gene for XLH was identified in 1995 and named phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) . The expression of PHEX is found in osteocytes, osteoblasts, and odontoblasts . Although PHEX protein shows homology to endopeptidases with single membrane-spanning region, it is not clear whether PHEX physiologically works as an endopeptidase. Hyp mouse, which has a deletion in portion of Phex gene, is known as a model of XLH. Several results suggest that hypophosphatemia in Hyp and XLH patients is caused by some humoral factor. For example, the crosstransplantaion of kidneys in wild-type and Hyp mice did not change their phenotypes . In addition, renal transplantation from a healthy donor to a patient with XLH did not correct renal phosphate wasting . It has been shown that serum FGF23 levels in most XLH patients are above the reference range [30, 31]. Serum FGF23 levels in Hyp mice are also elevated, and excess production of FGF23 is found particularly in bone of Hyp mice. These results indicate that the overexpression of FGF23 in bone is responsible for hypophosphatemic rickets/osteomalacia in patients with XLH and Hyp mice. Again, it remains to be clarified how PHEX protein regulates the synthesis of FGF23 in bone.
FD is a bone lesion in which medullary cavity is replaced by fibrous, osseous, and chondral tissues. FD occurs either as monostotic (70%–80%) or as polyostotic (20%–30%) form. MAS is a syndrome consisting of polyostotic fibrous dysplasia, skin hyperpigmentation (café-au-lait spots), and endocrine dysfunction, frequently seen in females as precocious puberty. MAS is caused by somatic mosaicism of cells harboring activating mutations in guanine nucleotide binding protein, alpha stimulating 1 (GNAS1) gene. These mutations are also observed in FD tissues without MAS. Approximately 50% of MAS/FD patients show hypophosphatemic rickets/osteomalacia. It was reported that FGF23 production is found in bone including regions of FD, and circulatory FGF23 levels are increased in MAS/FD patients who show hypophosphatemic rickets/osteomalacia . However, it is not demonstrated that enhanced cyclic AMP level actually increases FGF23 production, and the mechanism of FGF23 overproduction remains to be clarified.
TIO is a paraneoplastic syndrome usually associated with mesenchymal slow-growing tumors. Most tumors responsible for TIO are now pathologically classified as phosphaturic mesenchymal tumors, mixed connective tissue variant (PMTMCT). FGF23 was identified as a causative humoral factor for TIO, which is quite rare in childhood . FGF23 was shown to be abundantly expressed in tumors causing TIO [5, 32]. Circulatory FGF23 levels are elevated in virtually all patients with TIO . The surgical removal of responsible tumors results in normalization of FGF23 levels and cures this disease.
5. Hyperphosphatemic Diseases
Tumoral calcinosis is characterized by ectopic calcification especially around large joints. While the commonest form of tumoral calcinosis is observed in patients with end-stage renal disease undergoing dialysis, there are hereditary forms of tumoral calcinosis with normal renal function [33, 34]. Familial hyperphosphatemic tumoral calcinosis is a rare autosomal recessive disorder that is characterized by enhanced renal tubular phosphate reabsorption and rather high serum 1,25(OH)2D levels for hyperphosphatemia .
Biallelic mutations in GALNT3, FGF23, and Klotho have been shown to cause this hyperphosphatemic disease [35–38]. Mutations in GALNT3 and FGF23 have been shown to cause susceptibility of FGF23 protein to the processing between 179Arg and 180Ser resulting in low levels of full-length FGF23. GALNT3 encodes a protein called UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3. This is an enzyme involved in the synthesis of mutin-type O-linked glycans. Homozygous missense mutations in GALNT3 gene seem to cause impaired glycosylation of FGF23 protein making it susceptible for the processing. FGF23 mutations are postulated to cause the susceptibility by changing protein structure of FGF23. A homozygous mutation of Klotho has been shown to make the expression of Klotho protein to be markedly reduced, resulting in diminished ability of FGF23 protein to act on target organs .
FGF23 is marginally elevated in patients with hypoparathyroidism . High level of FGF23 is also found in patients with chronic kidney disease, especially in patients with end-stage renal disease . The high level of FGF23 in these diseases is regarded as a compensatory response to hyperphosphatemia or phosphate overload. However, it is still possible that some other factors associated with impaired renal function are contributing to the increase of FGF23 because FGF23 level is extremely high in some patients with end-stage renal disease.
FGF23 was shown to be produced by bone and act on kidney through a specific receptor system. In addition, excess and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. These results indicate that FGF23 works as a hormone, and several disorders of phosphate metabolism can be viewed as endocrine diseases. However, there still remain several important questions unanswered such as regulatory mechanisms of FGF23 production and signals beyond Klotho-FGFR1c that mediate FGF23 action. On the other hand, anti-FGF23 antibodies were already shown to increase serum phosphate and 1,25(OH)2D levels both in wild-type and Hyp mice [41, 42]. Like many other endocrine diseases, it may become possible to treat patients with abnormal phosphate metabolism by regulating the activity of this phosphotropic hormone.
This work was partly supported by Grants from Ministry of Education, Culture, Sports, Science and Technology of Japan and from Ministry of Health, Labor and Welfare of Japan.
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