Nat Rev Endo-'09
Published on: Mar 3, 2016
Transcripts - Nat Rev Endo-'09
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 5 | NOVEMBER 2009 | 611
Department of Oral
Medicine, Infection and
School of Dental
Medicine, Boston, MA,
Department of Oral
Medicine, Infection and
School of Dental
and Education Building,
Room #304, 190
Boston, MA 02115,
The FGF23–Klotho axis: endocrine regulation
of phosphate homeostasis
M. Shawkat Razzaque
Abstract | Appropriate levels of phosphate in the body are maintained by the coordinated regulation of the
bone-derived growth factor FGF23 and the membrane-bound protein Klotho. The endocrine actions of FGF23,
in association with parathyroid hormone and vitamin D, mobilize sodium–phosphate cotransporters that
control renal phosphate transport in proximal tubular epithelial cells. The availability of an adequate amount
of Klotho is essential for FGF23 to exert its phosphaturic effects in the kidney. In the presence of Klotho,
FGF23 activates downstream signaling components that influence the homeostasis of phosphate, whereas
in the absence of this membrane protein, it is unable to exert such regulatory effects, as demonstrated
convincingly in animal models. Several factors, including phosphate and vitamin D, can regulate the
production of both FGF23 and Klotho and influence their functions. In various acquired and genetic human
diseases, dysregulation of FGF23 and Klotho is associated with vascular and skeletal anomalies owing to
altered phosphate turnover. In this Review, I summarize how the endocrine effects of bone-derived FGF23, in
coordination with Klotho, can regulate systemic phosphate homeostasis, and how an inadequate balance of
these molecules can lead to complications that are caused by abnormal mineral ion metabolism.
Razzaque, M. S. Nat. Rev. Endocrinol. 5, 611–619 (2009); doi:10.1038/nrendo.2009.196
Phosphorus, a major mineral ion that is routinely con-
sumed through food, is usually associated with oxygen in
the form of phosphate. Phosphate is widely distributed
in the body and is an important factor in bone formation,
but is also involved in cell signaling, energy metabolism,
nucleic acid synthesis, and the maintenance of acid−base
balance (urinary buffering).1,2
The physiologic balance
of phosphate is maintained by the coordinated inter-
actions of the small intestine, bone, parathyroid gland
functional impairments in any of these
organs can lead to abnormal phosphate levels (Box 1).
For example, in most chronic renal diseases,9–11
renal function perturbs the homeostasis of phosphate, as
well as that of physiologic water, electrolytes, and mineral
As high as 70% of dietary phosphate can be absorbed
from the upper half of the intestine and then taken
up by the cells that need it; the remaining amount is
mostly excreted through urine. Of particular interest,
in response to the intestinal phosphate administration,
phosphaturia can occurwithout measurable changes in
plasma concentrations of phosphate and independentof
parathyroid hormone, as similar responses have also been
detected in parathyroidectomizedanimals. These obser-
vations implicate the putative existence of an intestinal
‘phosphate sensor’, which might send a hormonal signal
to stimulate urinary phosphate excretion immediately
after an intestinal phosphate load.12
Transepithelial phosphate transport in the intestine
(through enterocytes) and in the kidney (through proxi-
mal epithelial cells) is primarily mediated by proteins in
the sodium/phosphate cotransporter family (NaPi-2a,
NaPi-2b and NaPi-2c) that are expressed in the apical
membrane of the epithelial cells. More than 80% of
the filtrated phosphate in the kidneys is reabsorbed in the
proximal tubules through NaPi-2a and NaPi-2c. Various
endocrine factors, including parathyroid hormone,
active vitamin D metabolites and FGF23, can directly or
indirectly control NaPi activities to influence systemic
phosphate balance (Figure 1). In addition to parathyroid
hormone and vitamin D, numerous other hormones can
affect renal phosphate handling. Growth hormone,
insulin, and thyroid hormone can all increase phos-
phate reabsorption, whereas calcitonin, glucocorticoids,
and atrial natriuretic factor can decrease it, primarily by
influencing the activity of NaPi-2a.13,14
Among these factors, parathyroid hormone is one of
the most potent regulators of phosphate metabolism.
Parathyroid hormone can suppress the reabsorption of
phosphate in the proximal tubules by reducing NaPi-2a
and NaPi-2c activities. This reduction is achieved by
internalization of NaPi proteins from the lumen side of the
proximal tubular epithelial cells.15
can also mobilize phosphate from the bone into the blood-
stream, possibly by enhancing osteoclastic bone resorp-
In addition, parathyroid hormone can increase the
production of 1,25 dihydroxyvitamin D3 (calcitriol) by
The author declares associations with the following companies:
Daiichi Sankyo, Genzyme and Kyowa Hakko Kirin
Pharmaceuticals. See the article online for full details of the
612 | NOVEMBER 2009 | VOLUME 5 www.nature.com/nrendo
inducing the renal expression of 1-α hydroxylase, which
affects intestinal phosphate absorption.Two complemen-
tary systems might have a role in adapting acute or chronic
changes in dietary phosphate intake: chronic changes
might involve calcitriol-dependentchanges in NaPi trans-
whereas acute changes might be medi-
ated through an immediate hormonal response that is yet
to be determined.12
Intestinal phosphate uptake, therefore,
is a major regulatory factor that can control the physiologic
balance of serum phosphate level.
Cellular, intracellular, transcellular and pericellular
mineral ion transports are complex processes that are
FGF23 is a bone-derived growth factor that can influence the homeostasis
of phosphate and vitamin D
Systemic regulation of phosphate homeostasis by FGF23 is dependent
on the activity of the membrane protein Klotho
Determination of serum FGF23 levels might improve the diagnosis and prognosis
of various diseases associated with abnormal mineral ion metabolism, including
tumor-induced osteomalacia and chronic kidney diseases
Restoration of normal FGF23 activity, by targeting FGF23 or Klotho, might have
therapeutic benefits in diseases associated with abnormal mineral ion metabolism
Hyperphosphatemia might have more serious consequences in both skeletal and
nonskeletal tissues than usually appreciated
transport across renal proximal tubular epithelial cellsis
mostly driven by a high extracellularsodium concentra-
tion, which is thought to be maintained by the membrane-
-ATPase. Some experts have suggested
that the transmembrane protein Klotho can influence
-ATPase activity, which results in an increased
ion gradient and enhances transepithelial calcium
transport in the choroid plexus and the kidneys.18−20
Active regulation of phosphate homeostasis and its rela-
tion to calcium transport and balance are evolving areas
of research. In the following sections, I discuss the role of
the bone-derived growth factor FGF23 and the membrane
protein Klotho in the regulation of systemic phosphate
homeostasis, and the consequences of the inadequate
balance of these molecules.
The role of FGF23
A major breakthrough in understanding the active
regulation of phosphate homeostasis was accomplished
by the identification of FGF23.21,22
FGF23 is a ~30 kD
protein that is proteolytically processed to a ~18kD
N-terminal fragment and a ~12kD C-terminal fragment.
The receptor-binding domain of FGF23 is present in the
FGF23 is able to suppress the expression of NaPi-2a
and NaPi-2c cotransporters either directly, as shown by
or through affecting parathyroid hormone
activity, which induces urinary phosphateexcretion by
reducing NaPi-2a and NaPi-2c cotransporter activities.24
Transgenic mice that overexpress FGF23 have hypo-
phosphatemia owing to the suppression of renalNaPi co-
transporters, as well as reduced serum calcitriol levels and
skeletal mineral deposition defects in the formof rickets
FGF23 can also influence systemic
vitamin D activity by suppressing the renal expressionof
1α hydroxylase, which results in decreased production
In addition, FGF23 can reduce the activity of
and the resultant reduced vitamin D
activities might induce parathyroid hormone secretion and
concomitant phosphaturia. Some investigators claimed
that FGF23 can directly suppress parathyroid hormone
which should inhibit phosphaturia, possibly
moreover, secondary hyperparathyroidism develops in
patients with chronic kidney diseases (CKD), despite their
extremely high serum levels of FGF23. Further studies are
needed to determine the molecular interactions of FGF23
and parathyroid hormone that lead to biochemical changes
in various clinical disorders, including CKD.
Diseases related to increased FGF23 level
A number of other human diseases are associated with
increased FGF23 levels (Table 1). Vitamin-D-resistant ric-
kets or osteomalacia in patients with X-linked hypophos-
(which encodes a phosphate-regulating endopeptidase and
is homologous with other endopeptidase-genes that are
Box 1 | Potential causes of serum phosphate imbalance
Acidosis (respiratory or lactic acidosis, diabetic
Drug treatment (for example amphotericin B
Impairment of growth hormone secretion (acromegaly)
Impairment of thermoregulation (hyperthermia
Intestinal impairment (bowel infarction)
Impairment of parathyroid hormone secretion
(hypoparathyroidism or pseudo-hypoparathyroidism)
Phosphate-containing laxatives or enemas
Trauma (for example, burns or crush injuries)
Tumors (leukemia, lymphoma, bone tumors)
Vitamin D intoxication
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 5 | NOVEMBER 2009 | 613
levels of FGF23.31
In another inherited human disease,
autosomal dominant hypophosphatemic rickets (ADHR),
gain-of-functionmutations of FGF23 (which result in sub-
stitutions ofArg residues at 176and/or 179 to Gln or other
residues andprevent the proteolytic cleavage of FGF23) are
Furthermore, in some patients with epi-
dermal nevus syndrome, which can be related to activating
increased serum levels of FGF23 are
associated with renal phosphate wasting.33
Similarly, increased production of FGF23 by tumor
cells in patients with tumor-induced osteomalacia can
induce excessive renal phosphate wasting and mineraliza-
tion defects in the bone. These clinical symptoms can be
reversed by surgical removal of the FGF23-producing
A pathological role for FGF23 has also been sug-
gested in the McCune–Albright syndrome35
and in osteo-
in both conditions, increased serum
levels of FGF23 can cause hypophosphatemia. In osteo-
glophonic dysplasia, an autosomal dominant disorder
characterized by nonossifying bone lesions and abnormal
mineral ion balance, increased FGF23 levels are caused
by heterozygous, missense mutations in FGFR1 that lead
to constitutive activation of the FGF receptor.36
McCune-Albright syndrome is also a genetic disease that
plasia of the bones, and is caused by activating mutations
in the GNAS1 gene.
Hypophosphatemia in patients with autosomal reces-
sive hypophosphatemic rickets/osteomalacia (ARHR) has
also been attributed to high serum FGF23 levels.37
patients might have mutations inDMP-1, but the mecha-
nism by which these mutations can lead to increased
FGF23 production is not yet clear. In a related experi-
mental study, increased production of FGF23 was detected
in Dmp-1 knockout mice with hypophosphatemia, and
genetic deletion of Fgf23 in such mutants resulted in
similar hyperphosphatemia as that observed in Fgf23
single knockout mice.38
Thus, hypophosphatemia in
Dmp-1 knockout mice is though to be induced by the
increased FGF23 level.
Diseases related to decreased FGF23 level
Reduced FGF23 activity can also cause diseases in humans
(Table 1). For instance, patients with familial tumoral cal-
cinosis (FTC) usually develop hyperphosphatemia and
ectopic calcification owing to loss-of-function mutations
Similarly, mutations in GALNT3 gene, which
encodes the glycosyl transferase ppGaNTase 3 have also
been identified in patients with FTC.40
In these patients,
serum levels of intact FGF23 are reduced, whereas levels of
the processed, C-terminal FGF23 fragment are increased,
which suggests an accelerated proteolysis of full-length,
bioactive FGF23. Interestingly, ppGaNTase 3 has been
shown to specifically induce O-glycosylation of the
Thr178 residue, which is located in the proteolytic site
Similarly, Galnt3-knockout mice show an
impaired secretion of intact FGF23, despite an increased
expression of FGF23 in the bone, which indicates an
important in vivo role of GALNT3 in the processing and
secretion of FGF23.42
Together, these observations imply
that mutations in GALNT3 can impair O-glycosylation
Serum phosphate level
Phosphate excretion Phosphate absorption
Figure 1 | Serum phosphate lowering effects of FGF23.
FGF23 (produced in the bone) can suppress NaPi-2a and
NaPi-2c cotransporters, which results in increased renal
excretion of phosphate. Similarly, FGF23 can suppress
renal expression of 1-α hydroxylase, which leads to
reduced production of calcitriol and decreased intestinal
phosphate absorption, and subsequent reduced serum
levels of phosphate.
Table 1 | Diseases owing to dysregulation of FGF23
Human diseases Cause
Increased FGF23 activity
X-linked hypophosphatemia PHEX mutation
McCune-Albright syndrome GNAS1 mutation
Osteoglophonic dysplasia FGFR1 mutation
Epidermal nevus syndrome FGFR3 mutation
Tumor-induced osteomalacia FGF23-producing tumor
Decreased FGF23 activity
Familial tumoral calcinosis GALNT3 or FGF23
or KL mutation
The serum levels of both the C-terminal fragment of FGF23 and of intact
FGF23 are high in patients with familial tumoral calcinosis who carry a KL
mutation, whereas serum levels of C-terminal FGF23 are high and levels of
intact FGF23 are low-to-normal in patients with familial tumoral calcinosis
who carry GLANT3 or FGF23 mutations.
614 | NOVEMBER 2009 | VOLUME 5 www.nature.com/nrendo
of FGF23 in patients with FTC, and thereby increase the
susceptibility of FGF23 to proteolytic inactivation.
Studies of the human genetic disorders that influence
the functionality of FGF23 have substantially increased
our understanding of the regulation of systemic phosphate
homeostasis. However, the exact role and mechanisms by
which FGF23 regulation is perturbed in acquired human
diseases should be investigated further, particularly in
patients with renal diseases.43
FGF23 and chronic kidney disease
Patients with advanced stages of CKD have elevated
serum levels of FGF23, which increase progressively as
renal function declines. Intact FGF23 seems to be the
major circulating form that is present in patients with
CKD, although some studies have also reported the
presence of the C-terminal fragment of FGF23. Serum
measurements of FGF23 are usually performed using
either the Immunotopics assay, (San Clemente, CA, USA)
or the Kainos assay (Tokyo, Japan).44
serum levels of FGF23, patients with CKD develop hyper-
Inability of FGF23 to reduce or normalize
serum phosphate levels in patients with CKD can trigger
the development of secondary hyperparathyroidism.
However, the causes of elevated serum levels of FGF23
in patients with CKD are not clear. The potential mecha-
nisms include decreased renal clearance of FGF2346
increased production of FGF23 that counteract hyper-
phosphatemia; the second possibility is supported by
human studies where a high dietary phosphorus load
increased serum levels of FGF23.47
therapy in patients with CKD might also contribute to
increased serumlevels of FGF23.48
Saito and colleagues
have reported that both phosphorus andcalcitriol inde-
pendently increase circulating FGF23 levels.49
with CKD tend to have low levels of calcitriol and secon-
dary hyperparathyroidism. Whether increased levels
of FGF23 can influence this dysregulation is a complex
issue that should be investigated.As FGF23 can suppress
vitamin D activity,50
the increased levels of FGF23 in
patients with CKD might reduce vitamin D activity and
eventually facilitate the development of compensatory,
The endocrine functions of parathyroid hormone
contribute to the maintenance of phosphate balance by
promoting renal phosphate excretion, and might also
reduce urinary calcium excretion and stimulate the
renal production of active vitamin D metabolites.Never-
theless, even though serum parathyroid hormone levels
are high in patients with CKD, parathyroid hormone
fails to reduce serum phosphate levels in these patients.
Increased production of parathyroid hormone that
counteracts hyperphosphatemia could substantially
contribute to the development of secondary hyper-
Of particular interest, elevated level of
serum FGF23 is suggested to be an important predictor
of secondary hyperparathyroidism in patients who are
undergoing dialysis treatment.54
The interaction between
FGF23 and parathyroid hormone is a complex process
that is not yet clearly understood; experimental studies
have suggested that parathyroid hormone can increase
whereas others have found
that FGF23 can inhibit parathyroid hormone synthesis.25,26
Whether increased serum parathyroid hormone levels
can increase the production of FGF23 or vice versa in
patients with CKD who receive hemodialysis treatment
needs additional studies.
Hyperphosphatemia is an important determinant of
mortality in patients with CKD, irrespective of other
associated biochemical changes. However, serum phos-
phate level can be influenced by numerous factors,
including diet, the use of phosphate-lowering drugs, or
abnormal skeletal conditions. Serum phosphate level,
therefore, can be misleading in risk assessment, particu-
larly when they remain within the normal range. Some
studies have suggested that under normophosphatemic
conditions, serum level of FGF23 might be a better bio-
marker than serum phosphate level for risk assessment in
patients with CKD.57
A number of studies have suggested an association
between increased serum level of FGF23 and increased
mortality in patients with CKD, particularly in those who
The cause of this association
is not clear, but some studies have found a correlation
between elevated serum FGF23 level and an increased rate
of left ventricular hypertrophy.59,60
Although these associ-
ation studies are of interest, they do not provide enough
mechanistic evidence to prove that FGF23 directly affects
cardiovascular structural components, which influence
cardiac functions and, eventually, mortality.The available
(genetically altered) animal models might be able to show
a direct effect of FGF23 on cardiovascular structure and
function convincingly.Kl-deficient mice are characterized
by extremely high serum levels of FGF23 compared with
control mice, and early, sudden death (Figure 2), which
is linked to cardiac dysfunction of the sino-atrial node.61
Determining whether high serum levels of FGF23 con-
tribute to the cardiac dysfunction and early mortality of
Kl-deficient mice might help us understand the patho-
logic role of elevated serum levels of FGF23 in patients
The role of Klotho
Klotho is a type 1 membraneprotein, with a single trans-
membrane domain near its C-terminus that is hypo-
thesized to anchor the proteinto the membrane.18
cellular functions and cell–matrix interactions are per-
formed through membrane proteins, which consist of
transmembrane and anchored proteins.Type I membrane
proteins usually have a single transmembrane stretch
of hydrophobic amino acids, with the N-terminus
exposed to the extracellular side of the membrane and
the C-terminus exposed on the cytoplasmic side. If the
short transmembrane domain of Klotho is removed, the
remaining fragment (the secreted form) can be released
into the circulatory system.
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 5 | NOVEMBER 2009 | 615
The gene Kl, which encodes Klotho in the mouse is
located on chromosome 13q12 and has 5 exons and 4
The transcript of this gene is about 5.2kb. The
third exon of Kl can be alternatively spliced to generate
two transcripts, which encode the transmembrane and
secreted forms of Klotho.The transcript of the full-length
Kl encodes a protein of 1,014 amino acids and a molecu-
lar weight of 130kD (the transmembrane form), whereas
the truncated Kl encodes a protein of 550 amino acids
and a molecular weight of approximately 65–70kD (the
The full-length mouse Kl cDNA has around 93% and
80% homology with those of rat and human, respec-
whereas the mouse Klotho protein has around
94% and 80% homology with the rat and human pro-
The transmembrane form of the mouse Klotho
possesses a putative signal sequence at its N-terminus, a
putative transmembrane domain, and a short cytoplasmic
domain at the C-terminus. The extracellular domain of
Klotho consists of two internal repeats of about 550 amino
acids (KL1 and KL2) that share sequence homology with
β-glucosidase. Between two internal repeats (KL1 and
KL2), a short stretch of basic amino acids (Lys-Lys-Arg-
Lys) is included that forms a possible site for proteo-
lytic cleavage. This short stretch of basic amino acids is
present in the rat, human and mouse Klotho proteins.
The secreted form of mouse Klotho only contains the
N-terminal fragment, including its extracellular domain
One study has suggested that the metallo-
proteinases ADAM-10 and ADAM-17 are able to cleave
Klotho from the plasma membrane, and that insulin can
stimulate Klotho shedding.66
Klotho expression has been detected in the distal con-
mice exhibit increased renal expression of NaPi-2a and
NaPi-2c protein with concomitant hyperphosphatemia
(Figure3) and develop the same physical, biochemical, and
morphological characteristics as Fgf23-knockout mice.62
The identical phenotypes of these two separate knockout
lines eventually led to the identificationof Klotho as an
essential cofactor in FGF23 signalingpathways.67−71
In general, most FGFs bind to FGF receptors on the cell
surface and activate downstream signaling events that
exert diverse biological functions. FGF23 is a member
of the FGF19 subfamily, which also contains FGF19 and
FGF21, and has been shown to bind to multiple FGF
receptors, including FGFR1c, FGFR3c, and FGFR4.67,70,72,73
Follow-up studies, however, suggested that FGFR1 is the
principal mediator of the effects of FGF23 in vivo.74,75
Further research has suggested that Klotho can bind to
multiple FGF receptors, and that the Klotho−FGF recep-
tor complex binds to FGF23 with much higher affinity
than either the FGF receptor or Klotho alone.The binding
of this complex can then activate downstream signaling
events, as demonstrated by the activation ofEgr-1 and the
phosphorylation of FGF receptor substrate-2a, ERK, p38,
JNK, and AKT.67,70,76
Notably, these signaling phospho-
proteins have been detected only when cells were treated
with both FGF23 and Klotho, and not in cells that were
treated with FGF23 only. These results, along with earlier
observations, clearly suggest that the interaction of FGF23
and the FGF receptor and subsequent signaling activities
require Klotho as a cofactor.77
In response to elevated serum phosphate levels, FGF23
is produced in the bone and exerts endocrine effects in
the kidneys in coordination with Klotho, which is mostly
expressed in the distal tubular epithelial cells and pro-
motes renal phosphate excretion.The phosphate-lowering
effect of FGF23 is partly mediated through the reduced
expression of NaPi-2a and 1α hydroxylase in the proximal
1 3 5 7 9
Time after birth (weeks)
11 13 15 17 19 21
Figure 2 | Gross features, survival and serum FGF23 levels in Kl-knockout mice.
Compared with WT mice, Kl–/–
mice are smaller in size (a), have markedly elevated
serum levels of FGF23 (b) and have a shorter lifespan (around 15−20 weeks) (c).
The serum level of FGF23 was measured by enzyme-linked immunosorbent assay
using a commercial kit that detects the intact form of FGF23.*P<0.001 versus WT;
data presented as mean±SEM. Abbreviations: Kl–/–
, Kl-knockout; WT, wild type.
616 | NOVEMBER 2009 | VOLUME 5 www.nature.com/nrendo
tubular epithelial cells. Despite the fact that Klotho is
present only in the distal tubular epithelial cells, FGF23-
mediated phosphate metabolism takes place in the proxi-
maltubules. Of note, the FGF receptor 1 is also expressed
in distal tubules.75
The interaction of proximal and distal
tubules to facilitate FGF23-Klotho-mediated functions is
an important and unsolved issue, and an active area of
research.In one study, robust induction of phosphorylated
ERK1 (a marker of FGF23 bioactivity) was detected only
within Klotho-expressing distal tubules following FGF23
injection, which suggests that FGF23-mediated signaling
might be initiated in the distal convoluted tubule.78
studies have paved the way to a future, in-depth descrip-
tion of the role of Klotho in FGF23-mediated regulation
of phosphate homeostasis.
Systemic functions of FGF23–Klotho axis
Transgenic mice that overexpress humanFGF23 or mouse
Fgf23 develop hypophosphatemia owing to severe urinary
phosphate wasting, whereasFgf23-knockout mice develop
hyperphosphatemia owing to an increased renal uptake
of filtrated phosphate. A genetic restoration of the sys-
temic actions of human FGF23 in Fgf23-knockoutmice
reverses hyperphosphatemia to hypophosphatemia and
prevents associated complications, including ectopic cal-
These genetically modified animal models
have provided valuable insights intothe role of FGF23 in
regulating phosphate homeostasis, and some studies have
clearly demonstrated in vivo the importance of Klotho in
this regulation. For instance, serum phosphate levels are
substantially reduced following an injection of bioactive
FGF23 in either wild-type or Fgf23-knockout mice.68
wild-type and Fgf23-knockout mice both express endo-
genous Klotho, the exogenous FGF23 is able to influence
systemic phosphate homeostasis. In contrast, the injec-
tion of bioactive FGF23 protein into either Kl-knockout
mice or Fgf23/Kl double knockout mice does not produce
any obvious changes in the serum levels of phosphate.68
These observations imply that Klotho is essential for the
FGF23-mediated regulation of phosphate homeostasis.
strated in a genetically engineered, hypophosphatemic
These mice possess a mutation that
inactivates Phex, a phosphate-regulating gene that is
homologous to the endopeptidase-encoding genes that are
located on the Xchromosome.This mutation is associated
with severe hypophosphatemia secondary to excessive
urinary phosphate wasting, which is caused by increased
serum accumulation of FGF23. In vivo genetic manipula-
tion studies have shown that the inactivation of Klotho
in Phex–deficient mice results in hyperphosphatemia,
not hypophosphatemia, even though mice that are defi-
cient of both Phex and Kl have markedly elevated serum
levels of FGF23.79
The opposing phenotypes of these single
mutant and double mutant mice suggest that the disrup-
tion of Klotho-mediated pathways abrogates the hypo-
phosphatemic phenotype that is normally caused by the
increased serum levels of FGF23.80,81
Furthermore, genetic inactivation ofKl in FGF23 trans-
genic mice results in a phenotype that is consistent with
Klotho-deficiency, which again emphasizes the in vivo
importance of Klotho in the function of FGF23.82
humans, a homozygous, loss-of-function mutation inKL
causes tumoral calcinosis, severe hyperphosphatemia and
ectopic calcification despite high serum levels of FGF23 in
the affected patients.83
Together, these human and mouse
genetic studies provide compelling evidence that klotho
is essential in the FGF23-mediated regulation of systemic
phosphate homeostasis in vivo.
Nevertheless, under pathological conditions where the
concentration of FGF23 is extremely high, FGF23 might
exert nonspecific effects without klotho, as FGF23 can
bind to FGF receptors with low affinity in the absence of
Several in vitro studies also support the possi-
bility of such nonspecific responses. For instance, FGF23
has been shown to suppress osteoblast differentiation
and bone mineralization in fetal rat calvaria cells.84
Kl is not expressed in osteoblasts, any effect of FGF23 on
these cells would indicate that Klotho-independent effects
of FGF23 exist, unless bone cells express extremely low
levels of Klotho that are undetectable with existing tools.
In a similar study, FGF23 was shown to exhibit weak
proliferative effects on a murine bone-marrow-derived
pro-B cell line that overexpresses FGF receptors but does
not express Klotho.85
Figure 3 | Renal expression of NaPi-2a and serum levels of phosphate in Kl-knockout
mice. Compared with WT mice, Kl–/–
mice exhibit increased renal expression of
NaPi-2a (a and b) and hyperphosphatemia (c). Note that hyperphosphatemia is
observed in Kl–/–
mice by 3 weeks of age and their serum phosphate level remains
high for their entire lifespan. *P <0.05 versus WT; data presented as mean ± SEM.
, Kl-knockout; WT, wild type.
Kl–/– WT Kl–/– WT Kl–/–
a bWT Kl–/–
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 5 | NOVEMBER 2009 | 617
Future studies should determine whether extremely
high serum levels of FGF23 can lead to ectopic activation
of FGF receptors and induce cardiac morbidity in patients
with CKD. In this scenario, patients with CKD might
benefit from therapy that lowers FGF23 level. However,
a thorough understanding of the role of elevated serum
FGF23 levels in patients with CKD is needed before
any therapeutic strategy can be proposed. For example,
whether increased FGF23 level is a protective response (in
early stages) or an adverse effect (in later stages) in patients
with CKD is not clear. Moreover, vitamin D deficiency
has been linked to increased mortality in advanced CKD
and, as FGF23 can suppress the production of
active vitamin D metabolites, any detrimental effect of
FGF23 in these patients might be influenced by reduced
vitamin D activity.
As discussed above, the creation of Phex/Kl double
mutant mice has clearly demonstrated that the FGF23-
mediated hypophosphatemia in Phex-deficient mice
is Klotho-dependent. These genetic studies have pro-
vided in vivo evidence that suggests that Klotho might
be a potential therapeutic tool to manipulate FGF23
function, and direct manipulation of Klotho might be
used as a novel therapeutic strategy for FGF23-related
The clinical applica-
tion of a controlled reduction of FGF23 might be of
therapeutic benefit for patients with excessive urinary
phosphate wasting diseases, including ADHR, ARHR,
and XLH. Currently, treatments for these genetic hypo-
phosphatemic diseases, such as oral phosphate replace-
ment, are mostly palliative, and the prolonged use of these
therapies can lead to complications, notably secondary
hyperparathyroidism. Treatment of Phex-deficient mice
with anti-FGF23 antibodies inhibited the endogenous
FGF23 activities and resulted in increased serum levels of
In a similar study, inactivation of endogenous
FGF23 activity in Phex-deficient mice by manipulation
of Klotho’s function resulted in hyperphosphatemia,
even though Phex/Kl double mutant mice have markedly
elevated serum levels of FGF23.79
Finally, in contrast to
anti-FGF23 therapy, administration of exogenous, bio-
active FGF23 protein might help restore phosphate
balance and delay associated complications, such as the
ectopic calcifications in patients with FTC that are usually
caused by reduced FGF23 activity.
Exogenous FGF23 treatment has been shown to delay
the progression of renal failure induced by experimental
nephritis. However, this treatment also aggravated renal
osteodystrophy owing to reduced levels of calcitriol,
which demonstrates a potential limitation of FGF23
Renal osteodystrophy is often described as
a CKD and mineral and bone disorder. Of particular
interest, calcitriol can exert opposing effects on serum
phosphate levels: it can induce both FGF23 and Klotho to
increase urinary excretion of phosphate and lower serum
phosphate levels, but can also facilitate increased intesti-
nal absorption of phosphate to increase serum phosphate
levels (Figure 4).
The regulation of systemic phosphate homeostasis seems
to be strictly controlled by a limited number of factors,
as demonstrated by the opposing phenotypes of trans-
genic and knockout Fgf23-mutant mice, their similari-
ties with Kl-mutant mice, and—more importantly—the
corresponding clinical phenotype in hereditary diseases
that are caused by FGF23 or KL mutations in humans
The overlapping phenotypes and the
lack of redundancy in phenotypes of Fgf23-mutant mice
with Kl-mutant mice, suggest that the biological network
that actively regulates phosphate homeostasis consists of a
limited number of essential factors.Our understanding of
the essential in vivo role of FGF23 in maintaining systemic
phosphate homeostasis has laid the foundation for future
work to determine the therapeutic benefit of manipulat-
ing the FGF23−Klotho network in patients with excessive
urinary phosphate-wasting diseases. In addition, serum
FGF23 measurements might have both diagnostic and
determine the underlying causes of diseases that are associ-
ated with abnormal mineral ion metabolism. For instance,
osteomalacia, and pretreatment serum level of FGF23
might be a good predictor of the efficacy of vitamin D
therapy in patients who receive dialysis, as well as for the
future development of refractory hyperparathyroidism.54
Hypophosphatemia in the early posttransplant period
in patients who receive renal transplant is more strongly
associated with increased level of FGF23 than that of para-
Similarly, another study suggests that
FGF23 is independently and negatively associated with
the calcification of arteries in the hand, but not of the
aorta in patients with CKD who undergo hemodialysis,
and proposed that plasma FGF23 levels can be a reli-
able marker for medial, peripheral artery calcification in
Furthermore, extensive cardiovascular
calcification, which is a leading cause of death in patients
Serum phosphate level
Serum phosphate level
Urinary phosphate excretion
Figure 4 | The endocrine effects of vitamin D on
phosphate metabolism. Calcitriol increases urinary
excretion of phosphate by inducing the expression of both
FGF23 (in bone) and Klotho (in kidney), which results in
decreased serum phosphate levels. Calcitriol can also
facilitate increased intestinal absorption of phosphate,
which increases serum phosphate levels.
618 | NOVEMBER 2009 | VOLUME 5 www.nature.com/nrendo
with CKD who undergo hemodialysis, is associated with
high serum FGF23 levels.58,95–98
In conclusion, experimental studies have provided
compelling evidence of the in vivo importance of Klotho
in FGF23-mediated regulation of systemic phosphate
homeostasis. Translation of this research to new thera-
pies for patients who suffer from the complications of
abnormal mineral ion metabolism will be a challenging
yet clinically rewarding effort.99
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2009 and focussing on FGF23 was performed in MEDLINE
and PubMed. The search terms used were “FGF23”,
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language, full-text papers. I also searched the reference lists
of identified articles for further papers and looked for the
abstracts of similar topics presented in scientific meetings.
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The author thanks T. Nakatani and M. Ohnishi (Harvard
School of Dental Medicine, Boston) for technical
assistance and T. Taguchi (Nagasaki University, Japan)
for continued help and encouragement. Some of the
original research that formed the basis of this Review is
supported by a grant (R01-DK077276 to M.S.R.) from
the National Institute of Diabetes and Digestive and
Kidney Diseases, and institutional support from
Nagasaki University School of Biomedical Science
and Harvard School of Dental Medicine.