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Annals of Medicine.

2008; 40: 8291


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REVIEW ARTICLE

Calcium and phosphate homeostasis: Concerted interplay of new


regulators

KIRSTEN Y. RENKEMA, R. TODD ALEXANDER, RENE J. BINDELS & JOOST


G. HOENDEROP

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

Introduction fibroblast growth factor member 23 (FGF23) and


klotho have been identified as new players essential
The tight control of plasma calcium (Ca2+) and to the regulation of Ca2+ and Pi homeostasis (35).
phosphate (Pi) levels is essential to the performance Remarkably, large alterations in dietary Pi and Ca2+
of many vital physiological functions. Muscle intake produce only small alterations in the
contraction, blood clotting and neuronal excitation circulating levels of these ions due to the combined
all require Ca2+, whereas Pi is vital to intracellular action of these signaling molecules on bone,
signaling, as a component of membrane lipids and intestinal, and renal Ca2+ and Pi transport (2,6,7).
to build the backbone of DNA. Moreover, sig- At times these regulatory processes are over-
nificant elements of bone are Ca2+ and Pi (1,2). whelmed producing disturbances in Ca2+ and Pi
Several organs contribute to the exquisite regula- homeostasis. Patients with chronic renal insuffi-
tion of Ca2+ and Pi homeostasis by facilitating ciency (CRI) highlight pathophysiology compli-
intestinal absorption, bone (de)mineralization, and cated by altered Ca2+ and Pi handling. These
renal excretion/reabsorption of both ions. individuals have a decreased glomerular filtration
Regulation of these processes occurs by a number rate, a decreased circulating plasma 1,25-dihydrox-
of hormones. The biologically active form of yvitamin D3 (1,25(OH)2D3) level and consequently
vitamin D (1,25-dihydroxyvitamin D3), parathyroid develop secondary hyperparathyroidism (8). This
hormone (PTH), and calcitonin have been exten- review highlights the physiological mechanisms
sively studied in this regard. More recently, governing Ca2+ and Pi transport, two intimately

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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related processes, and the clinical implications of


their altered regulation. Key messages
N Maintenance of normal phosphate (Pi) and
2+ calcium (Ca2+) homeostasis is crucial to
Physiology of Ca and Pi homeostasis many vital physiologic processes including
2+ cellular signaling, DNA structure, bone
Ingested Ca and Pi are absorbed by different
segments of the small intestine. The active absorp- mineralization, muscle contraction, blood
tion of sodium (Na+) throughout the entire course of clotting, and neuronal excitation.
the intestine results in a large net water absorption. N Fibroblast growth factor member 23
This mainly occurs in the small intestine, where (FGF23), klotho, parathyroid hormone,
Ca2+ and Pi are concomitantly taken up in a passive, and 1,25-dihydroxyvitamin-D3 are key
paracellular manner, down their concentration regulators of Ca2+ and Pi homeostasis.
gradient. The active transcellular absorption of Pi Their concerted action alters (re)absorption
occurs predominately from the ileum (9), whereas from intestine, kidney, and bone via recently
active Ca2+ transport takes place largely from the identified pathways.
duodenum (10). N The concerted interplay of klotho and
The vast majority of whole body Ca2+ and Pi is FGF23 contributes substantially to the
stored as the mineral hydroxylapatite in the skeleton. regulation of renal Pi handling and may
In blood 45% of Ca2+ is present in a free, ionized provide a therapeutic target for chronic renal
form, 45% is bound to proteins, and a small fraction, insufficiency-related hyperphosphatemia and
10%, forms complexes with anions including citrate, other disorders involving disturbances of Pi
sulphate, and phosphate. Plasma Pi is present in its balance.
inorganic form and as a component of several
organic substances including sugars, phosphopro-
teins, and high-energy phosphates. The tightly entry mediated by the epithelial Ca2+ channel,
regulated renal elimination of electrolytes, including TRPV6 (12). Ca2+ is subsequently shuttled to the
Ca2+ and Pi, maintains a near constant plasma level basolateral side of the cell via the Ca2+-binding
protein, calbindin-D9K. This process is completed
of ions and significantly contributes to whole body
by transport of Ca2+ back into the bloodstream via
homeostasis. Free Ca2+ and Pi are filtered by the
the plasma membrane Ca2+-adenosine triphospha-
glomerulus and gain entry into the renal tubule. In
tase (PMCA1b) (13).
contrast to the gastrointestinal system, Pi is largely
absorbed in a transcellular, Na+-dependent manner The Na+-dependent Pi cotransporter type IIb
in the proximal tubule (PT). This process is (NaPi-IIb) is localized to the brush border of ileum.
There it is responsible for active Pi transport from
dependent on the electrochemical gradient present
the intestinal lumen into the blood (9,14). NaPi-IIb
for Na+ (11). Renal Ca2+ absorption occurs para-
is also present, although to a significantly decreased
cellularly in the PT and the thick ascending limb of
extent, in duodenum and jejunum, consistent with
Henle (TAL). A small (10%15%) highly regulated
less overall active Pi reabsorption from these locales
amount of Ca2+ is actively absorbed from the distal
(9). The mechanism and identity of the molecules
convoluted tubule (DCT) and the connecting tubule
responsible for the extrusion of Pi back into the
(CNT) (10,11). A diverse array of ion transport
blood is not known at present.
proteins, localized to the apical and basolateral
After intestinal absorption into the blood, Ca2+
membranes of intestinal and renal epithelia, mediate
and Pi are filtered across the glomerulus into the
this active transport of Ca2+ and Pi. The entry of
tubular lumen of the nephron. Along the course of
these ions, from lumina into the cytosol of the
the nephron passive, paracellular Ca2+ absorption
specific epithelium, is tightly regulated and repre-
occurs from the PT and TAL. A three-step process
sents the rate-limiting step in transcellular Ca2+ and
mediates the active Ca2+ reabsorption mechanism
Pi (re)absorption (10).
from the DCT and CNT. First, Ca2+ enters the cell
via the epithelial Ca2+ channel TRPV5 (and to a
lesser extent TRPV6). Then Ca2+ diffuses through
Ca2+ and Pi transport proteins
the cytosol via calbindin-D28K, to the basolateral
The ability of the small intestine to actively absorb side of the cell. There, Ca2+ is extruded into the
Ca2+ and Pi is hormonally regulated and occurs from peritubular capillary by the Na+-Ca2+-exchanger
the duodenum and ileum, respectively. Active (NCX1) and PMCA1b (10). Active Pi absorption
intestinal Ca2+ absorption begins with its luminal occurs in the PT of the kidney via the
84 K. Y. Renkema et al.
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Na+-dependent Pi cotransporters, NaPi-IIa and stimulation of Ca2+ (re)absorption (3,2124).


NaPi-IIc. Both display high expression levels in the Hypercalcemia has the opposite effect. This state
early segments (S1 and S2) of the PT (2,11,1517). activates the CaSR, thereby inhibiting PTH release
Figure 1 summarizes the transcellular pathways of and stimulating the secretion of calcitonin from the
Ca2+ (A) and Pi (B) transport in kidney and parafollicular cells of the thyroid. Calcitonin
intestine. decreases osteoclast-mediated bone resorption and
promotes lowering the blood Ca2+ concentration
(25).
Hormonal regulation of transcellular Ca2+ Estrogen contributes importantly to Ca2+ home-
(re)absorption ostasis by promoting bone mineralization and
stimulating renal TRPV5 expression. This results
Exquisite regulation of TRPV5 and TRPV6 activity 2+
in increased active Ca reabsorption, independently
is essential to whole body Ca2+ homeostasis. Here,
of 1,25(OH)2D3 (2628). PTH, 1,25(OH)2D3, and
we review the regulatory effects of the classically
estrogen exert their effect on renal-mediated Ca2+
described hormones: PTH, 1,25(OH)2D3, and
handling by altering, at the transcriptional level,
calcitonin on active Ca2+ transport processes. Later
the expression of Ca2+ transporters (7). This has
we will discuss the newly identified regulators of
been confirmed, in vivo, where a direct stimulatory
Ca2+ homeostasis: tissue kallikrein (TK), the antia-
effect of PTH on renal Ca2+ transporter expression
ging hormone klotho, and estrogen. Central to this
levels was demonstrated in PTH-supplemented
process is the Ca2+-sensing receptor (CaSR), which
parathyroidectomized rats (29), and where the
is expressed in the parathyroid gland where it senses
dietary supplementation of Ca2+ and the adminis-
blood Ca2+ levels (18,19). In response to changes in
tration of estrogen to ovariectomized rats was shown
blood Ca2+ concentrations, the CaSR regulates the
to alter renal TRPV5 expression, all independently
release of PTH into the circulation (Figure 2).
of 1,25(OH)2D3 (7,23,28).
Specifically, hypocalcemia inhibits the CaSR that
The TK knockout (TK2/2) mouse displays
in turn promotes the secretion of PTH. This
significant renal Ca2+ wasting compared to control
hormone stimulates Ca2+ mobilization from bone
mice, implicating an important role for TK in the
and the conversion of inactive vitamin D to
regulation of active Ca2+ reabsorption (30). In 2006,
1,25(OH)2D3 by the renal cytochrome P450 enzyme
Gkika et al. described the molecular mechanism
25-hydroxyvitamin D3-1a-hydroxylase (1aOHase) through which TK stimulates TRPV5-mediated
(20). Increased 1,25(OH)2D3 levels activate vitamin active Ca2+ reabsorption. TK, a proteolytic enzyme
D receptor (VDR)-mediated gene transcription, that is secreted into the tubular fluid by renal
resulting in an increased transcription of Ca2+ epithelial cells, activates the bradykinin receptor
transport proteins. Ultimately this results in the stimulating the phospholipase C/1,2-diacylglycerol/
protein kinase C (PLC/DAG/PKC) pathway. This
results in increased plasma membrane expression of
TRPV5, possibly due to an inhibition of TRPV5
endocytosis. Regardless of the exact mechanism, TK
increases TRPV5-mediated Ca2+ transport (31).
Recently the antiaging hormone klotho has also
been implicated in the regulation of the Ca2+
balance. Klotho knockout (klotho2/2) mice display
hypercalcemia, hyperphosphaturia, hypercalciuria,
Figure 1. Transcellular Ca2+ and Pi transport. Active Ca2+ and Pi
transport across renal and intestinal epithelium. A: Ca2+ influx is and other manifestations resembling aging (32).
mediated by TRPV5 in the renal distal convoluted and connecting Chang et al. demonstrated that klotho stimulates
tubules and TRPV6 in the duodenum. Subsequently, Ca2+ is TRPV5-mediated Ca2+ transport in vitro, revealing a
transported across the cell to the basolateral membrane by Ca2+- novel regulatory mechanism of active Ca2+ transport
binding proteins calbindin-D28K (kidney) and calbindin-D9K
(intestine). Extrusion into the blood takes place via the plasma
(33). Klotho is a type I transmembrane protein with
membrane Ca2+-ATPase (PMCA1b) in the intestine and sodium- b-glucuronidase activity. This activity is contained in
Ca2+ exchanger (NCX1) and PMCA1b in the kidney. B: The ileal the extracellular domain that can be secreted into
brush border, sodium-dependent Pi cotransporter, NaPi-IIb, the blood, urine, and cerebrospinal fluid (32,34).
mediates entry of Pi into enterocytes. In the proximal tubules, Klotho hydrolyzes extracellular N-linked oligosac-
NaPi-IIa and NaPi-IIc are responsible for Pi entry into the tubular
epithelial cells. The transport mechanisms involved in basolateral charides present on TRPV5, entrapping the channel
extrusion of Pi into blood are unknown both in the intestine and in the plasma membrane. This stimulatory effect of
kidney. klotho on TRPV5 substantiates the important role of
Calcium and phosphate homeostasis 85
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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
Downloaded By: [Hoenderop, Joost G.] At: 19:01 21 February 2008

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.
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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.
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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.
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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,
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