Article

Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active.

Endocrine Unit, Thier 10, 50 Blossum Street, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
The Journal of clinical endocrinology and metabolism (impact factor: 6.5). 12/2009; 95(2):578-85. DOI:10.1210/jc.2009-1603 pp.578-85
Source: PubMed

ABSTRACT Context: Fibroblast growth factor 23 (FGF23) regulates phosphorus homeostasis and vitamin D metabolism. Circulating FGF23 levels are elevated in inherited and acquired hypophosphatemic disorders that can cause rickets or osteomalacia. Particularly increased concentrations of FGF23 are observed in patients with chronic kidney disease (CKD), in which increased FGF23 is associated with more rapid disease progression, improved bone mineralization, the development of left ventricular hypertrophy, and increased mortality. Objective: Our objective was to determine whether the markedly elevated levels of immunoreactive FGF23 in CKD represent accumulation of intact, biologically active hormone, C-terminal cleavage fragments, or both. Design: Biologically active FGF23 in plasma from CKD patients treated by peritoneal dialysis was quantified using a cell-based Egr-1 reporter assay; bioactive FGF23 levels were compared with those measured with immunometric FGF23 assays detecting either intact hormone alone or intact hormone and C-terminal fragments. Setting and Patients: Adult and pediatric patients with end-stage renal disease treated with peritoneal dialysis participated in the study at a tertiary referral center. Results: Serially diluted patient samples revealed levels of bioactive FGF23 that ran in parallel to CHO cell-derived recombinant human FGF23. FGF23 bioactivity was inhibited by an anti-FGF23 antibody. Levels of bioactive and immunoreactive FGF23 were tightly correlated, and Western blot analysis of FGF23 immunoprecipitated with anti-FGF23 antibodies from plasma of dialysis patients revealed only a single prominent protein band, which was indistinguishable from recombinant intact FGF23, without clear evidence for FGF23 fragments. Conclusions: Our results provide strong evidence for the conclusion that virtually all circulating FGF23 in dialysis patients is intact and biologically active.

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    Article: Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.
    Takashi Shimada, Takanori Muto, Itaru Urakawa, Takashi Yoneya, Yuji Yamazaki, Katsuya Okawa, Yasuhiro Takeuchi, Toshiro Fujita, Seiji Fukumoto, Takeyoshi Yamashita
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    ABSTRACT: FGF-23 is involved in the pathogenesis of two similar hypophosphatemic diseases, autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced osteomalacia (TIO). We have shown that the overproduction of FGF-23 by tumors causes TIO. In contrast, ADHR derives from missense mutations in FGF-23 gene. However, it has been unclear how those mutations affect phosphate metabolism. Therefore, we produced mutant as well as wild-type FGF-23 proteins and examined their biological activity. Western blot analysis using site-specific antibodies showed that wild-type FGF-23 secreted into conditioned media was partially cleaved between Arg(179) and Ser(180). In addition, further processing of the cleaved N-terminal portion was observed. In constrast, mutant FGF-23 proteins found in ADHR were resistant to the cleavage. In order to clarify which molecule has the biological activity to induce hypophosphatemia, we separated full-length protein, the N-terminal and C-terminal fragments of wild-type FGF-23. When the activity of each fraction was examined in vivo, only the full-length FGF-23 decreased serum phosphate. Mutant FGF-23 protein that was resistant to the cleavage also retained the activity to induce hypophosphatemia. The extent of hypophosphatemia induced by the single administration of either wild-type or the mutant full-length FGF-23 protein was similar. In addition, implantation of CHO cells expressing the mutant FGF-23 protein caused hypophosphatemia and the decrease of bone mineral content. We conclude that ADHR is caused by hypophosphatemic action of mutant full-length FGF-23 proteins that are resistant to the cleavage between Arg(179) and Ser(180).
    Endocrinology 09/2002; 143(8):3179-82. · 4.46 Impact Factor
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Keywords

anti-FGF23 antibody
 
bioactive FGF23
 
Biologically active FGF23
 
C-terminal cleavage fragments
 
CHO cell-derived recombinant human FGF23
 
chronic kidney disease
 
circulating FGF23
 
Circulating FGF23 levels
 
CKD patients
 
dialysis patients
 
end-stage renal disease
 
hypophosphatemic disorders
 
immunoreactive FGF23
 
increased FGF23
 
pediatric patients
 
peritoneal dialysis
 
rapid disease progression
 
recombinant intact FGF23
 
tertiary referral center
 
Western blot analysis