Beruflich Dokumente
Kultur Dokumente
REVIEW ARTICLE
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands
Abstract
Calcium (Ca2+) and phosphate (Pi) are essential to many vital physiological processes. Consequently the maintenance of
Ca2+ and Pi homeostasis is essential to a healthy existence. This occurs through the concerted action of intestinal, renal, and
skeletal regulatory mechanisms. Ca2+ and Pi handling by these organs is under tight hormonal control. Disturbances in their
homeostasis have been linked to pathophysiological disorders including chronic renal insufficiency, kidney stone formation,
and bone abnormalities. Importantly, the kidneys fine-tune the amount of Ca2+ and Pi retained in the body by altering their
(re)absorption from the glomerular filtrate. The ion transport proteins involved in this process have been studied
extensively. Recently, new key players have been identified in the regulation of the Ca2+ and Pi balance. Novel regulatory
mechanisms and their implications were introduced for the antiaging hormone klotho and fibroblast growth factor member
23 (FGF23). Importantly, transgenic mouse models, exhibiting disturbances in Ca2+ and Pi balance, have been of great
value in the elucidation of klotho and FGF23 functioning. This review highlights the current knowledge and ongoing
research into Ca2+ and Pi homeostasis, emphasizing findings from several relevant knockout mouse models.
Key words: 1,25-Dihydroxyvitamin-D3, calcium, fibroblast growth factor 23, klotho, phosphate, sodium-phosphate
cotransporter, TRPV5, TRPV6
Correspondence: Joost G. J. Hoenderop, 286 Physiology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, NL-6500 HB Nijmegen, The
Netherlands. Fax: +31-24-3616413. E-mail: j.hoenderop@ncmls.ru.nl
ISSN 0785-3890 print/ISSN 1365-2060 online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.1080/07853890701689645
Calcium and phosphate homeostasis 83
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Figure 2. Key players in Ca2+ and Pi homeostasis. The concerted interplay of intestinal uptake, reabsorption in kidney, and bone
(de)mineralization establishes the maintenance of a normal Ca2+ and Pi balance. The calcium sensing receptor (CaSR), present in the
thyroid gland, senses blood Ca2+ levels and triggers the secretion of the calcitropic hormones parathyroid hormone (PTH) and calcitonin.
Ovarian-produced estrogen stimulates Ca2+ reabsorption also. Similar hormones are involved in the regulation of Pi balance. Blood Pi levels
are controlled by PTH, 1,25(OH)2D3, klotho, and fibroblast growth factor member 23 (FGF23). A negative feedback mechanism prevents
the accumulation of FGF23 and klotho since 1aOHase-mediated 1,25(OH)2D3 production is inhibited by FGF23 and klotho.
this antiaging hormone in Ca2+ homeostasis, speci- dietary Pi intake are known to alter Pi (re)absorption
fically by altering the luminal membrane Ca2+ (36). An increased intestinal NaPi-IIb expression
permeability of the DCT and the cortical collecting can be stimulated by either 1,25(OH)2D3 and/or low
duct (CCD) (33). Alternatively, the mechanism of Pi intake, ultimately resulting in elevated blood Pi
hypercalciuria observed in klotho2/2 mice has been (6). Conversely, PTH decreases blood Pi levels by
suggested to be the result of decreased proximal inhibiting Pi reabsorption from the PT. This occurs
Ca2+ absorption because of a decreased Na+K+- via an acute redistribution of NaPi-IIa proteins from
ATPase activity (35). the brush border to intracellular lysosomes, targeting
them for degradation. The overall effect of PTH is
therefore to lower blood Pi levels by stimulating Pi
Hormonal regulation of transcellular Pi excretion (37).
(re)absorption Recently, FGF23 has been labeled a phosphato-
Our understanding of the hormonal control of Pi nin, due to its role in Pi homeostasis (5,3840).
balance is rapidly evolving. Klotho and FGF23 were Injection of FGF23 into mice results in hypopho-
recently identified as new key players involved in Pi sphatemia by stimulating renal Pi excretion. This is
regulation, adding to what had already been achieved by decreasing the expression of renal NaPi-
delineated about the classical PTH/1,25(OH)2D3 IIa and NaPi-IIc and inhibiting 1aOHase produc-
regulatory pathway. PTH, 1,25(OH)2D3, and tion. The role of FGF23 in human Ca2+ and Pi
86 K. Y. Renkema et al.
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homeostasis has been firmly established by genetic serum Ca2+ concentration without altering the total
linkage analysis. Inactivating mutations in FGF23 amount in blood. Symptoms and findings of
have been identified in patients with tumoral hypercalcemia include fatigue, electrocardiogram
calcinosis causing hyperphosphatemia, and activat- abnormalities, nausea, vomiting, constipation, anor-
ing mutations have been shown to cause autosomal exia, abdominal pain, hypercalciuria, and conse-
dominant hypophosphatemic rickets (ADHR) (41 quently kidney stone formation. Treatment of
44). FGF23 is a secreted, transmembrane protein hypercalcemia depends on the severity of the
produced in bone osteoblasts (45,46), which can abnormality and ranges from dietary adaptation to
bind to and activate FGF receptors (FGFRs) the administration of calcimimetic compounds that
(47,48). Further, the involvement of klotho in activate the CaSR in the parathyroid glands, redu-
FGF23 signaling was suggested as klotho2/2 mice cing blood PTH levels (56). Hypocalcemia can
and FGF23 knockout (FGF232/2) mice exhibit result in muscle cramping, depression, psychosis,
many common phenotypic features including hyper- and seizures. Causes include decreased Ca2+ absorp-
phosphatemia (32,38,49). This was confirmed in tion due to a poor intake, 1,25(OH)2D3 deficiency
2006, when Kurosu et al. demonstrated that klotho or resistance, lack of sunlight, decreased bone
forms a complex with FGFRs. This new complex resorption, a complication of thyroid surgery (i.e.
binds FGF23 with a higher affinity than either the parathyroidectomy), or renal Ca2+ wasting. Oral
FGFR or klotho alone (50). Two separate groups Ca2+ and 1,25(OH)2D3 supplementation and ultra-
extended this observation by showing that direct violet light exposure are the current treatments for
binding of klotho to the FGFR1(IIIc) subtype hypocalcemia.
converts this receptor into a specific FGF23 receptor
(48,51). In addition, Ogawa et al. demonstrated that
another member of the klotho family, b-klotho, can Hypercalciuria
function as a cofactor in FGF21 signaling, through a
Hypercalciuria is a risk factor for renal Ca2+ stone
similar interaction as with klotho and FGF23 (52).
formation and therefore contributes to this signifi-
FGF21 is expressed predominantly in the liver and is
cant health and socioeconomic problem (57,58). In
a metabolic regulator of glucose uptake in adipo-
the United States (US) more than 5% of the
cytes, consequently it provides a potential therapeu-
population will develop a clinically significant
tic target in diabetes mellitus (53). Other FGF
episode of kidney stone disease in their lifetime of
family members have been implicated in varying
which the economic impact is approximately $2
signal transduction pathways throughout the
billion annually (59,60). Hypercalciuria has been
body (54). A recent report revealed that FGF7 is
classified into at least three different forms.
overexpressed in tumors associated with renal Pi
Absorption hypercalciuria is due to Ca2+ hyperab-
wasting and osteomalacia (55). FGF7 inhibits Pi
sorption from the GI tract, renal hypercalciuria is the
transport in renal epithelial cells, although the exact
result of a defect in renal Ca2+ reabsorption, whereas
molecular mechanisms involved still need to be
resorptive hypercalciuria manifests urinary Ca2+
elucidated. Further investigation is necessary to
wasting secondary to increased bone degradation.
determine whether other FGF superfamily members
Other than these three types of hypercalciuria, the
are involved in the regulation of Ca2+ and Pi
largest group of patients with this disorder lack an
homeostasis.
explanation for their increased Ca2+ excretion and
have been classified as having idiopathic hypercal-
ciuria. Individuals with a family history of nephro-
Hypercalcemia and hypocalcemia
lithiasis are themselves prone to develop kidney
Disturbances in both serum and whole body Ca2+ stones. This strongly suggests that genetic factors are
levels can cause severe pathological conditions, the involved in the pathogenesis of idiopathic hypercal-
etiology of which is both complex and variable. ciuria (61). There is a myriad of potential dis-
Hypercalcemia can result from Ca2+ hyperabsorp- turbances in Ca2+ homeostasis that can cause
tion from the gastrointestinal (GI) tract, decreased hypercalciuria. Thus, hypercalciuria may be mono-
urinary excretion, or an increased resorption from genic, polygenic, or multifactorial in its etiology. As
bone. Elevated serum PTH levels, secondary to TRPV5 as well as TRPV6 gene ablation in mice
hyperparathyroidism or a hypophosphatemic state, leads to severe forms of hypercalciuria, these
will cause increased Ca2+ absorption from the GI channels were proposed as candidate genes for
tract. Increased Ca2+ loss from bone is caused by hypercalciuria (1,62). To date, mutation analyses
elevated PTH and/or 1,25(OH)2D3 levels or skeletal of the TRPV5-encoding gene has not revealed a
metastasis, while severe dehydration will increase primary role for TRPV5 in autosomal dominant
Calcium and phosphate homeostasis 87
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idiopathic hypercalciuria (63). However, the invol- diseases. CRI patients ultimately develop end stage
vement of TRPV5 or TRPV6 in hypercalciuria has renal disease and require renal replacement therapy,
not been definitively excluded. Specific single i.e. dialysis or kidney transplantation. In order to
nucleotide polymorphisms (SNPs) or combinations minimize the burden of this disease it is imperative
of SNPs in TRPV5/TRPV6 may modulate channel to attempt normalization of the Ca2+ and Pi balance
activity, and might therefore be responsible for in these patients (70).
altered renal Ca2+ excretion (64). Further investiga- Elevated blood FGF23 levels are detectable in CRI
tion is necessary to identify mutations in TRPV5 and patients with secondary hyperparathyroidism. This is
TRPV6 associated with disease. thought to represent a compensatory mechanism in an
attempt to excrete excess Pi and thus lower blood Pi
levels. The klotho2/2 mice exhibit increased blood
Hyperphosphatemia and hypophosphatemia FGF23 levels as well, possibly due to their apparent
hyperphosphatemia (71,72). As klotho has been
Autosomal dominant hypophosphatemic rickets
implicated in the stimulation of TRPV5-mediated
(ADHR) is a hereditary disorder characterized by
Ca2+ reabsorption and in the regulation of FGF23-
bone malformation and renal Pi wasting. Activating
mediated Pi reabsorption, both klotho and FGF23 may
mutations in the FGF23 gene have been identified in
play significant roles in the pathogenesis, treatment
these patients (41,65). Related diseases include X-
options and prediction of the prognosis of CRI (7375).
linked hypophosphatemia (XLH) and hereditary
hypophosphatemic rickets with hypercalciuria
(HHRH); both are characterized by disturbances
in Pi homeostasis. Tumor-induced osteomalacia Lessons from TRPV5 and TRPV6 knockout
(TIO) is characterized by hypophosphatemia sec- mice
ondary to renal Pi wasting and reduced blood
The generation and characterization of TRPV5
1,25(OH)2D3 levels (66,67). Whilst the molecular
knockout (TRPV52/2) mice confirmed this epithe-
identity of all the molecules responsible for these
lial Ca2+ channel to be the gatekeeper of active Ca2+
clinical disorders have yet to be identified, in a few
reabsorption (1). TRPV52/2 mice display severe
instances genes involved in the maintenance of Pi
hypercalciuria compared to control (TRPV5+/+)
homeostasis have been implicated other than FGF23
mice that are normocalcemic. The knockout mice
(68,69). Hypophosphatemia causes decreased bone
display hypervitaminosis D and upregulation of
mineralization and subsequently bone fragility, pain,
intestinal TRPV6 and calbindin-D9K, as a compen-
rickets, and growth retardation (69). Treatment is
satory mechanism for their severe renal Ca2+
aimed at the replacement of Pi and/or 1,25(OH)2D3.
wasting. Cross-breeding of TRPV52/2 and
Deactivating mutations in FGF23 cause hyper-
1aOHase knockout (1aOHase2/2) mice was per-
phosphatemic tumoral calcinosis, characterized by
formed in order to address the role of the increased
hypervitaminosis D and increased intestinal and
blood 1,25(OH)2D3 levels in these animals. TRPV5/
renal Pi absorption (43). Consistent with this,
1aOHase double knockout mice have decreased
FGF232/2 mice exhibit severe hyperphosphatemia
intestinal TRPV6 and calbindin-D9K expression,
further substantiating the regulatory role of FGF23
hypocalcemia, and severe bone abnormalities com-
in Pi homeostasis (49). In humans, renal insuffi-
pared to TRPV52/2 mice. These findings support
ciency, malignancy, drug abuse, or hypoparathyr-
the notion that the hypervitaminosis D observed in
oidism can lead to hyperphosphatemia. Treatment is
TRPV52/2 mice is responsible for the upregulation
with Pi binders or directed at the primary cause.
of intestinal Ca2+ transport proteins, and the
consequent intestinal Ca2+ hyperabsorption, likely
as compensation for the renal Ca2+ leak (76).
CRI
Notably, TRPV52/2 mice have acidic urine and
CRI is the progressive loss of renal function evinced are polyuric relative to their control littermates (1).
by a decreasing glomerular filtration rate. Clinical Both of these symptoms would act to promote the
symptoms and findings include hypertension, excretion of large amounts of Ca2+ without it being
edema, hyperkalemia, hypocalcemia secondary to a precipitated in the collecting ducts. TRPV52/2 mice
decreased serum 1,25(OH)2D3 level, secondary display significant hyperphosphaturia, predisposing
hyperparathyroidism, and hyperphosphatemia. them to an increased risk of Ca2+ phosphate
Disorders with disturbances in both Ca2+ and Pi precipitation. The molecular mechanism responsible
homeostasis, of which CRI is just one, can lead to for the renal Pi leak in TRPV52/2 mice remains
severe bone, cardiovascular, and other systemic unknown.
88 K. Y. Renkema et al.
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The TRPV52/2 mice show a greatly diminished role for this hormone in Pi homeostasis (38,49).
expression of calbindin-D28K. To assess whether the The FGF232/2 mice display hyperphosphatemia,
absence of TRPV5 or the downregulation of hypervitaminosis D, growth retardation and limb
calbindin-D28K was responsible for the phenotype deformation. Crossing the FGF232/2 mice with
observed in the TRPV52/2 animals, double knock- 1aOHase-deficient animals rescued much of this
out mice, for both TRPV5 and calbindin-D28K, were phenotype (79). Specifically the atherosclerosis and
generated. These mice do not display a further ectopic skeletal and soft tissue calcifications
increase in their Ca2+ loss relative to TRPV52/2 observed in the FGF232/2 animals are absent from
mice, confirming that TRPV5 and not calbindin- the FGF23/1aOHase double knockout mice. The
D28K is the rate-limiting transporter in active Ca2+ double knockout animals also have increased survi-
reabsorption (77). val. Of note the phenotype is not rescued comple-
In vivo studies of specific knockout mice models tely, the FGF23/1aOHase double knockout mice
significantly contribute to our knowledge of renal have a further reduction in bone mineral density in
and intestinal Ca2+ handling. Recently, Bianco et al. comparison to the FGF232/2 mice. Together these
generated the TRPV6 knockout (TRPV62/2) mouse findings strongly suggest that the aging-like features,
in order to assess the role of this channel in intestinal disturbed electrolyte levels, and impaired skeleto-
Ca2+ absorption in vivo and its involvement in other genesis in FGF232/2 mice are the result of increased
organ systems (62). Surprisingly, these mice display blood 1,25(OH)2D3 levels (79,80). To further
skin abnormalities due to a decreased Ca2+ content elucidate the role of 1,25(OH)2D3 action in
in their epidermis and have impaired fertility. FGF232/2 mice, Hesse and co-workers cross-bred
Consistent with known TRPV6 localization the FGF232/2 mice with VDR knockout (VDR2/2)
knockout animals exhibit defective intestinal Ca2+ mice (81). FGF23/VDR double knockout mice
absorption as well as significant hypercalciuria and display a similar phenotype to the VDR2/2 mice,
decreased bone mineralization compared to control suggesting that the aging-like symptoms in FGF232/
littermates (62). Further, TRPV62/2 mice have 2
mice depend upon intact signaling through the
secondary hyperparathyroidism and hypervitamino- VDR (82). It is known that FGF23 expression is
sis D such that they are normocalcemic. These itself regulated by dietary Pi and 1,25(OH)2D3,
findings indicate that TRPV6 is central to suggesting a regulatory feedback mechanism in
1,25(OH)2D3-regulated Ca2+ absorption and overall which 1,25(OH)2D3 stimulates FGF23 production,
Ca2+ homeostasis. Finally, the exhibition of abnorm- that in turn inhibits 1aOHase, thereby decreasing
alities in multiple organs in TRPV62/2 mice under- circulating 1,25(OH)2D3 levels (83,84).
lines the importance of this channel in other body Klotho2/2 mice display a phenotype similar to
tissues. While TRPV5 clearly functions as a gate- FGF232/2 mice, which includes hyperphosphatemia,
keeper of active Ca2+ reabsorption from the lumen of hypervitaminosis D and bone abnormalities (32).
DCT and CNT, these recent findings suggest that The fact that the interplay of klotho and FGFRs is
TRPV6 may be an important regulator of Ca2+ essential for FGF23 functioning and the finding that
transport during embryonic and placental develop- both klotho2/2 and FGF232/2 mouse strains display
ment. Maintenance of normal Ca2+ levels is crucial comparable symptoms indicates that this newly
for physiological functioning of the uterus and identified klotho/FGF23 regulatory pathway is essen-
placenta, including both smooth muscle contraction tial to Pi homeostasis (48,50). Klotho2/2 mice also
and embryo implantation. Recently, Lee et al. demonstrate other phenotypic features not described
demonstrated that estrogen regulates TRPV6 in FGF232/2 mice, including pulmonary, neuronal,
expression levels during pregnancy, which is impor-
and skin disorders, implying that klotho may interact
tant for normal uterine function (78). Studies of
with other FGFRs throughout the body (32,50). How
TRPV62/2 mice during embryogenesis and devel-
klotho causes these additional phenotypic features
opment will be important to elucidate the exact role
and whether other FGF family members mediate
of TRPV6 and of its contribution to Ca2+ home-
them requires further investigation.
ostasis during different stages of organogenesis,
especially in the intestine and kidney.
Outlook
The work described in this review has greatly
Insights into Pi and Ca2+ homeostasis from
increased our knowledge of Ca2+ and Pi home-
FGF23 and klotho knockout mice
ostasis; however, several questions remain.
The recent generation of FGF232/2 mice, by two Identification of the antiaging hormone klotho as a
independent research groups, confirmed a central modulator of TRPV5 activity and its interaction with
Calcium and phosphate homeostasis 89
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FGFRs permitting increased FGF23 signaling have 9. Radanovic T, Wagner CA, Murer H, Biber J. Regulation of
been major breakthroughs in the understanding of intestinal phosphate transport. I. Segmental expression and
adaptation to low-Pi diet of the type IIb Na+-Pi cotransporter
both Ca2+ and Pi handling. An important tool in the in mouse small intestine. Am J Physiol Gastrointest Liver
elucidation of these research questions has been the Physiol. 2005;288:G496500.
use of knockout animal models. In this regard, it 10. Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption
remains a challenge to determine the exact role of across epithelia. Physiol Rev. 2005;85:373422.
1,25(OH)2D3 in both klotho- and FGF23-mediated 11. Murer H, Hernando N, Forster I, Biber J. Proximal tubular
phosphate reabsorption: molecular mechanisms. Physiol Rev.
signaling. It will be through further investigation of 2000;80:1373409.
these newly identified regulatory pathways, includ- 12. Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H,
ing klotho, FGF23, and 1,25(OH)2D3, that a clearer Brown EM, et al. Molecular cloning and characterization of a
understanding of how the body controls Ca2+ and Pi channel-like transporter mediating intestinal calcium absorp-
balance will be achieved. This knowledge will be tion. J Biol Chem. 1999;274:2273946.
13. Hoenderop JG, Bindels RJ. Epithelial Ca2+ and Mg2+
crucial for the manipulation of either klotho or
channels in health and disease. J Am Soc Nephrol.
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Biber J. Characterization of a murine type II sodium-
Acknowledgements phosphate cotransporter expressed in mammalian small
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This work was financially supported in part by grants
15. Collins JF, Ghishan FK. Molecular cloning, functional
from the Dutch Kidney Foundation (C03.6017 and expression, tissue distribution, and in situ hybridization of
C06.2170), the Netherlands Organization for the renal sodium phosphate (Na+/Pi) transporter in the
Scientific Research (Zon-Mw 016.006.001, NWO- control and hypophosphatemic mouse. FASEB J.
ALW 814.02.001, NWO-CW 700.55.302), and the 1994;8:8628.
16. Hernando N, Gisler SM, Pribanic S, Deliot N, Capuano P,
Dutch Stomach-Intestine-Liver foundation (MWO
Wagner CA, et al. NaPi-IIa and interacting partners. J
03-19). J. Hoenderop and R. T. Alexander are Physiol. 2005;567:216.
supported by an EURYI and a CIHR Clinician- 17. Forster IC, Hernando N, Biber J, Murer H. Proximal tubular
Scientist award, respectively. We thank the members handling of phosphate: A molecular perspective. Kidney Int.
of our laboratory for valuable discussion and advice. 2006;70:154859.
18. Chang W, Pratt S, Chen TH, Nemeth E, Huang Z,
Shoback D. Coupling of calcium receptors to inositol
phosphate and cyclic AMP generation in mammalian cells
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