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FGF23 and syndromes of abnormal renal phosphate handling.

ABSTRACT: Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by 1,25(OH)(2)-vitamin D (1,25(OH)(2)D), dietary and circulating phosphate and possibly PTH. FGF23 was discovered as the humoral factor in tumors that causes hypophosphatemia and osteomalacia and through the identification of a mutant form of FGF23 that leads to autosomal dominant hypophosphatemic rickets (ADHR), a rare genetic disorder. FGF23 appears to be mainly secreted by osteocytes where its expression is up-regulated by 1,25(OH)(2)D and probably by increased serum phosphate levels. Its synthesis and secretion is reduced through yet unknown mechanisms that involve the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), dentin matrix protein 1 (DMP1) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Consequently, loss-of-function mutations in these genes underlie hypophosphatemic disorders that are either X-linked or autosomal recessive. Impaired O-glycosylation of FGF23 due to the lack of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 3 (GALNT3) or due to certain homozygous FGF23 mutations results in reduced secretion of intact FGF23 and leads to familial hyperphosphatemic tumoral calcinosis. FGF23 acts through FGF-receptors and the coreceptor Klotho to reduce 1,25(OH)(2)D synthesis in the kidney and probably the synthesis of parathyroid hormone (PTH) by the parathyroid glands. It furthermore synergizes with PTH to increase renal phosphate excretion by reducing expression of the sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Loss-of-function mutations in these two transporters lead to autosomal recessive Fanconi syndrome or to hereditary hypophosphatemic rickets with hypercalciuria, respectively.

SUBMITTER: Bergwitz C

PROVIDER: S-EPMC5234086 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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FGF23 and syndromes of abnormal renal phosphate handling.

Bergwitz Clemens C Jüppner Harald H

Advances in experimental medicine and biology 20120101

Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by 1,25(OH)(2)-vitamin D (1,25(OH)(2)D), dietary and circulating phosphate and possibly PTH. FGF23 was discovered as the humoral factor in tumors that causes hypophosphatemia and osteomalacia and through the identification of a mutant form of FGF23 that leads to autosomal dominant hypophosphatemic rickets (ADHR), a rare genetic disorder. FGF23 appears to be mainly se ...[more]

PMID: 22396161

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Project description:Excess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X-linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross-sectional study (n =?74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23-dependent hypophosphatemia (n =?27), hypoparathyroidism (HOPT; n =?17), and chronic kidney disease (n =?30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20??g daily was self-administered for 28?days by one case of X-linked hypophosphatemia with hypoparathyroidism (XLH-HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28?days, TmP/GFR was lowered from 1.10?mmol/L to 0.48?mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

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FGF23 and syndromes of abnormal renal phosphate handling.

Publications

FGF23 and syndromes of abnormal renal phosphate handling.

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