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Endocrine FGFs and Klothos pp 41–64Cite as

FGF23 and Syndromes of Abnormal Renal Phosphate Handling

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 728))

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)2D), 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)2D 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)2D 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.

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Authors and Affiliations

  1. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Clemens Bergwitz & Harald Jüppner

  2. Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Harald Jüppner

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  1. Clemens Bergwitz
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  1. Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA

    Makoto Kuro-o MD, PhD

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Bergwitz, C., Jüppner, H. (2012). FGF23 and Syndromes of Abnormal Renal Phosphate Handling. In: Kuro-o, M. (eds) Endocrine FGFs and Klothos. Advances in Experimental Medicine and Biology, vol 728. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0887-1_3

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