The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasis

Razzaque, Mohammed S.; Lanske, Beate

doi:10.1677/joe-07-0095

Cited by 206 publications

(166 citation statements)

References 65 publications

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“…FGF23 activates FGF receptors, which require the presence of the co-receptor, KLOTHO, forming a FGF23-KLOTHO-FGFR1c complex, necessary for the transduction of the FGF23 signal, which results in phosphorylation of ERK (Pp44/42) and down-regulation of NPT2a (5,34). To evaluate whether the FGF23-KLOTHO axis is involved in renal regulation of phosphate homeostasis in TgHMW mice, mRNA levels of whole kidneys were determined by real-time PCR.…”

Section: Resultsmentioning

confidence: 99%

Nuclear Isoforms of Fibroblast Growth Factor 2 Are Novel Inducers of Hypophosphatemia via Modulation of FGF23 and KLOTHO

Xiao

Naganawa

Lorenzo

et al. 2010

Journal of Biological Chemistry

118

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FGF2 transgenic mice were developed in which type I collagen regulatory sequences drive the nuclear high molecular weight FGF2 isoforms in osteoblasts (TgHMW). The phenotype of TgHMW mice included dwarfism, decreased bone mineral density (BMD), osteomalacia, and decreased serum phosphate (P i ). When TgHMW mice were fed a high P i diet, BMD was increased, and dwarfism was partially reversed. The TgHMW phenotype was similar to mice overexpressing FGF23. Serum FGF23 was increased in TgHMW mice. Fgf23 mRNA in bones and fibroblast growth factor receptors 1c and 3c and Klotho mRNAs in kidneys were increased in TgHMW mice, whereas the renal Na shown that FGF23 is the phosphaturic factor (5) responsible for autosomal dominant hypophosphatemic rickets (6) and tumorinduced osteomalacia (7). FGF23 also mediates phosphatewasting disorders, such as X-linked hypophosphatemic rickets/ osteomalacia, the most common cause of vitamin D-resistant rickets (5). Loss of function mutations in PHEX, a phosphateregulatory gene with homology to endopeptidases on the X-chromosome, have been identified in X-linked hypophosphatemic rickets/osteomalacia (8); however, the mechanism by which this elevates FGF23 levels remains unclear. Autosomal recessive hypophosphatemic rickets/osteomalacia, caused by loss of function mutations in DMP1 (dentin matrix protein), is also associated with increased FGF23 (9). Increased FGF23 may occur in McCune-Albright syndrome due to a somatic gain of function mutation in GNAS1 arising during embryogenesis, characterized by chimeric distribution of hyperpigmented skin lesions, fibrous dysplasia of bone, and, often, hypophosphatemia (5). Murine models of this group of disorders include the FGF23 transgenic mouse, a model of autosomal dominant hypophosphatemic rickets (10); the Hyp mouse, a homologue of X-linked hypophosphatemic rickets/osteomalacia with a Phex deletion (11); and the Dmp1 null mouse, a model of autosomal recessive hypophosphatemic rickets/osteomalacia (12). These murine homologues demonstrate many of the phenotypic changes of the human disorders, including elevated serum FGF23.Another FGF ligand, FGF2 (fibroblast growth factor-2) is widely expressed and is a mitogen for many cell types, including osteoblasts and chondrocytes (1,13,14). The FGF2 gene encodes multiple FGF2 high molecular weight (HMW) protein isoforms expressed from unique CUG alternative translation start sites located 5Ј to the classical AUG initiation codon for the 18-kDa low molecular weight (LMW) exported isoform (1,

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Section: Resultsmentioning

confidence: 99%

Nuclear Isoforms of Fibroblast Growth Factor 2 Are Novel Inducers of Hypophosphatemia via Modulation of FGF23 and KLOTHO

Xiao

Naganawa

Lorenzo

et al. 2010

Journal of Biological Chemistry

118

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“…28,29 Such FGF23-mediated hypophosphatemia is an alpha-klotho-dependent phenomenon, and miscommunication of FGF23 and alpha-klotho can lead to dysregulation of renal phosphate homeostasis. 1,14,30,31 Renal Phosphate Regulation Under normal physiologic conditions, the kidneys maintain serum phosphate balance by fine-tuning urinary phosphate excretion. Filtrated phosphate is reabsorbed in the renal proximal tubular epithelial cells using sodium-dependent phosphate (Na/Pi) cotransporters [32][33][34] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

Brown

2015

BoneKEy Reports

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Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1a(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders.

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“…Various hyperphosphatemic and hypophosphatemic disorders have been shown to be directly related to altered FGF23 levels in the circulation. (1)(2)(3)(4) FGF23 is known to regulate blood Pi by decreasing the expression of the Pi transporter genes, Npt2A and Npt2C, in renal proximal tubule cells, thereby reducing renal ARHR), (9,10) tumor-induced osteomalacia (TIO), (8) and fibrous dysplasia of bone (FD). (11) Conversely, low levels of iFGF23 and elevated levels of cFGF23 are found in familial tumoral calcinosis (FTC) and hyperphosphatemic hyperostosis syndrome (HHS).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of FGF23 processing in fibrous dysplasia

Bhattacharyya

Wiench

Dumitrescu

et al. 2012

Journal of Bone and Mineral Research

107

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Fibroblast growth factor-23 (FGF23) is a phosphate-and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase Nacetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 þ iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G s a that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G s a mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients. ß

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The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasis

Cited by 206 publications

References 65 publications

Nuclear Isoforms of Fibroblast Growth Factor 2 Are Novel Inducers of Hypophosphatemia via Modulation of FGF23 and KLOTHO

Nuclear Isoforms of Fibroblast Growth Factor 2 Are Novel Inducers of Hypophosphatemia via Modulation of FGF23 and KLOTHO

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

Mechanism of FGF23 processing in fibrous dysplasia

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