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Review
. 2007 Jul;16(4):311-8.
doi: 10.1097/MNH.0b013e3281c55eca.

Mineral metabolism and aging: the fibroblast growth factor 23 enigma

Beate Lanske  1 , M Shawkat Razzaque
Affiliations
Review

Mineral metabolism and aging: the fibroblast growth factor 23 enigma

Beate Lanske et al. Curr Opin Nephrol Hypertens. 2007 Jul.

Abstract

Purpose of review: The regulation of phosphate homeostasis was thought to be passively mediated by the calciotrophic hormones parathyroid hormone and 1,25(OH)2D3. This article summarizes the emerging trends that show an active regulation of phosphate homeostasis by fibroblast growth factor 23 (FGF-23) - a process fairly independent of calcium homeostasis - and how altered mineral ion metabolism may affect the aging process.

Recent findings: A major breakthrough in FGF-23 biology has been achieved by the demonstration of strikingly similar physical/biochemical phenotypes of Fgf-23(-/-) and klotho hypomorph mice, which eventually led to the identification of klotho as a cofactor in FGF-23 and its receptor interactions. Furthermore, FGF-23 has emerged as a counter regulator of the renal 1alpha(OH)ase and sodium-phosphate cotransporter activities to modulate phosphate homeostasis. Finally, studies point towards a role of dentine matrix protein 1 in affecting phosphate homeostasis, in coordination with FGF-23.

Summary: Recent mouse genetic studies have broadened our understanding of biochemical/molecular pathways involved in phosphate homeostasis, and linked FGF-23 to such regulation. Understanding the molecular interactions of essential calcium and phosphate regulators will enhance our knowledge of the coordinated regulation of mineral ion metabolism, and will help to redefine the molecular pathology of age-associated lesions accompanied by abnormal mineral ion metabolism such as vascular calcifications and osteoporosis.

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Figures

Figure-1
Figure-1
Immunolocalization of NaPi2a in control (A) and Fgf-23 null mice kidney (B). Note a markedly increased expression of NaPi2a in the luminal side of the proximal tubular epithelial cells of Fgf-23 null mice (B). Increased expression of NaPi2a causes increased renal uptake of phosphate, leading to hyperphosphatemia in Fgf-23 null mice.
Figure-2
Figure-2
Simplified schematic diagram of renal regulation of calcium (Ca) and phosphate (Pi) homeostasis. Vitamin-D could exert stimulatory effects on klotho, FGF-23 and TRPV-5 [48,68,69]; TRPV-5 could induce renal calcium uptake through involving calbindin-D28k [70], while, FGF-23 could induce renal phosphate wasting through influencing the renal NaPi system [13,71], and thereby maintaining physiologic inverse Ca/Pi balance. Serum level of Ca/Pi has direct and indirect feedback through PTH on vitamin-D activities. Klotho by influencing biological activities of both TRPV-5 [72] and FGF-23 [4] could delicately fine tune the physiologic balance of Ca/Pi. There are other molecules that play important roles in regulation of Ca/Pi homeostasis, but to keep the diagram simple, we just cited the most essential factors.
See this image and copyright information in PMC

References

    1. ADHR_Consortium: Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR Consortium. Nat Genet. 2000;26:345–348. - PubMed
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    1. Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature ageing-like phenotype in fibroblast growth factor 23 null mice is a vitamin-D mediated process. FASEB J. 2006;20:720–722. This is the one of the earliest reports suggesting strikingly similar physical, biochemical and morphological phenotypes of klotho and Fgf-23 ablated mice; based on preliminary observations the authors speculated an existence of a common hormonal signaling cascade for klotho and FGF-23, which was scientifically validated by subsequent studies.

    1. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–774. A role of klotho in FGF-23 and its receptor interaction has been demonstrated.

    1. Kuro-o M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens. 2006;15:437–441. - PubMed

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