Prie_EU_Renal.qxp 9/7/07 10:37 am Page 28
Phosphorus Control
1 alpha-hydroxylase in mice (Razzaque 2005, ADHR Consortium).
11
Until hyperphosphataemia.
7,10–13
These data indicate that FGF23 acts like a
recently, NPT2b was thought to play a central role in intestinal absorption hormone – it targets organs at a distance from its site of production and
of phosphate. However, the recent identification of mutations in its gene the controlled parameters exert a feedback on FGF23 synthesis.
in humans has cast doubt on this assertion. Indeed, subjects carrying
NPT2b mutations present pulmonary alveolar microlithiasis, but under FGF23 circulates as two forms: a 32kd peptide – which is the full-length
current conditions exhibit normal plasma phosphate concentration and and, probably, active protein – and two by-products resulting from the
renal phosphate reabsorption. proteolytic cleavage at a specific site. The enzyme that degrades FGF23
in vivo has not yet been identified, but the glycosylation of FGF23
The third family of phosphate transporters is made up of ubiquitously
expressed sodium-phosphate carriers called inorganic phosphate
transporters (PiT). Two PiT proteins are present in mammalian – PiT1 and
PiT2. They are ubiquitously expressed; however, most tissue preferentially
Other phosphaturic factors have been
synthesises one of these transporters. They seem to be mandatory for
phosphate entry in cells, but their role is probably not to participate in identified, but they do not seem to
general phosphate homeostasis.
have hormone characteristics.
Hormones That Control Phosphate Homeostasis
The binding of PTH to its receptor on renal proximal tubular cells
diminished NPT2a expression and renal phosphate reabsorption. The role
of PTH is to control plasma-ionised calcium concentration – it releases increases its stability. The uridine diphosphate-N-acetyl-d-
calcium and, consequently, phosphate from bone. In order to prevent galactosamine/polypeptide N-acetylgalactosaminyl transferase 3
calcium and phosphate from precipitating in blood vessels, PTH increases (GALNT3) is a ubiquitously expressed enzyme that glycosylates FGF23.
14
urinary phosphate excretion. However, this function is not intended to
maintain normal plasma phosphate concentration. Other phosphaturic factors have been identified, but they do not seem to
have hormone characteristics. These peptides include secreted frizzled-
The presence of factors that control plasma phosphate concentration has related protein-4 (sFRP4), FGF7, phosphate-regulating gene with
been suspected for a long time, and these factors were given the generic homologies to endopeptidases on the X chromosome (PHEX), dentin
name of phosphatonins. The identification of the first phosphaturic matrix protein-1 (DMP)-1, matrix extracellular phosphoglycoprotein
peptide, FGF23, occurred in 2000.
3
This protein belongs to the fibroblast (MEPE). Their physiological functions are still under investigation, but it is
growth factor family because of its structure; however, as far as we known that they play a role in bone mineralisation and some of them
know, it does not directly induce cell growth but controls phosphate alter circulating FGF23 concentration by unknown mechanisms.
homeostasis. FGF23 is the most potent known inhibitor of 1 alpha-
hydroxylase, the enzyme that converts 25-OH vitamin D into its active Identified Mechanisms of Abnormal Phosphate Control
metabolite 1.25-(OH)
2
vitamin D or calcitriol. FGF23 also stimulates 24
hydroxylase, which generates two inactive metabolites 24,25(OH)
2
D and Mutations in Sodium-phosphate Transporter Genes
1,24,25(OH)
3
D.
4
As previously mentioned, the decrease in calcitriol Mutations in the gene coding for NPT2a and NPT2c proteins have been
concentration diminishes intestine phosphate absorption and contributes identified in humans.
15–18
Heterozygous or homozygous mutations of
to the decrease in plasma phosphate concentration. It also alters calcium these transporters lead to losses of function. The patient phenotypes
absorption, which stimulates PTH secretion, hence contributing to develop hypophosphataemia due to impaired renal phosphate
phosphate elimination in urine. reabsorption, renal calcium lithiasis, bone demineralisation or rickets.
Mice with targeted disruption of the NPT2a gene also exhibit
The mechanism by which FGF23 inhibits NPT2a and NPT2c expression in hypophosphataemia, increased urinary phosphate excretion and bone
the kidney is not yet understood. Recently published data indicate that abnormalities.
19,20
Interestingly, the disruption of the gene encoding the
Klotho, an ageing-related protein, converts FGF-receptor subtypes into NHERF1 protein in mice gives a phenotype similar to that observed in
specific FGF23 receptors.
5,6
However, in the kidney Klotho is expressed in NPT2a knock-out mice due to impaired expression of NPT2a at the brush-
the distal but not in the proximal tubule, where NPT2a and NPT2c are border membrane of renal proximal tubular cells.
21,22
NHERF1 is a PDZ
expressed. It is also unclear whether FGF23 action on renal phosphate protein that interacts with NPT2a
1
and also type-one PTH receptors,
reabsorption requires the presence of PTH. Indeed, plasma FGF23 modifying its response to PTH.
23
concentration is increased in patients with hypoparathyroidism, but fails
to normalise circulating phosphate concentration.
7
By contrast, patients Mutations in NPT2b gene have recently been reported. The patients have
with a normal parathyroid gland and increased FGF23 concentrations normal plasma phosphate concentration, renal phosphate transport is
exhibit marked hypophosphataemia, as observed in tumour-induced normal and they do not have renal lithiasis. However, they exhibit lung
osteomalacia or autosomal dominant hypo-phosphataemic rickets microlithiasis due to abnormal reclaiming of phosphate liberated from
(ADHR).
8,9
phospholipids in the alveolar surfactant.
24
FGF23 mRNA is detected in bone cells – osteoblasts and osteocytes – Alterations of Circulating FGF23 Levels
the liver, the kidneys and the thyroid. FGF23 synthesis in bone Oversecretion of FGF23 is observed in tumour-inducing osteomalacia –
is increased by calcitriol treatment, high phosphate content, diet and due to tumoural mesenchymal cells – as well as in McCune-Albright
28 EUROPEAN RENAL DISEASE 2007
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