Does Fgf23–klotho activity influence vascular and soft
tissue calcification through regulating mineral ion
Fahad Memon1, Mohga El-Abbadi2, Teruyo Nakatani1, Takashi Taguchi3, Beate Lanske1and
M. Shawkat Razzaque1,3
1Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA;2Department of
Bioengineering, University of Washington, Seattle, Washington, USA and3Department of Pathology, Nagasaki University School of
Biomedical Science, Nagasaki, Japan
Recent studies describe a novel role of fibroblast growth
factor-23 (Fgf23)–klotho activity in the systemic regulation of
calcium and phosphate homeostasis. Both Fgf23 and klotho
ablated mice develop extensive vascular and soft tissue
calcification. Inability to clear the required amount of
phosphate by the kidney, due to the absence of Fgf23–klotho
activity, leads to increased accumulation of serum phosphate
in these genetically modified mice, causing extensive
calcification. Serum calcium and 1,25 hydroxyvitamin D levels
are also elevated in both Fgf23 and klotho ablated mice.
Moreover, increased sodium phosphate co-transporter
activity in both Fgf23 and klotho ablated mice increases renal
phosphate reabsorption which in turn can facilitate
calcification. Collectively, these observations bring new
insights into our understanding of the roles of the
Fgf23–klotho axis in the development of vascular and soft
Kidney International advance online publication, 4 June 2008;
KEYWORDS: Fgf23; klotho; calcification; hyperphosphatemia; NaPi2a
FIBROBLAST GROWTH FACTOR-23
Fibroblast growth factor-23 (FGF23) is an approximately
30-kDa secreted protein that is mostly synthesized by the
osteocytes in the bone.1,2FGF23 is a master in vivo regulator
of phosphate homeostasis. Under physiological conditions, it
controls renal phosphate excretion according to the need of
the body through the regulation of the renal sodium-
dependent phosphate co-transporters NaPi2a and NaPi2c.3,4
Genetic defects in the FGF23 gene can produce distinct
human diseases. For instance, gain-of-function mutations in
FGF23 are responsible for the clinical symptoms observed in
patients suffering from autosomal dominant hypophospha-
temic rickets.5These mutations prevent the proteolytic
cleavage of the FGF23 protein, leading to its increased
biological activity and resulting in severe renal phosphate
wasting. Similarly, increased serum levels of FGF23 in
patients with oncogenic osteomalacia are found to be the
causative factor for tumor-induced renal phosphate wasting.6
Patients affected by X-linked hypophosphatemia, a dominant
disorder caused by inactivating mutations of the gene
encoding PHEX (the phosphate-regulating gene with homo-
logies to endopeptidases on the X chromosome), exhibit
increased serum FGF23 levels, phosphaturia, and osteoma-
lacia.7A similar phosphate wasting effect, due to increased
FGF23 serum levels, has been detected in patients with
autosomal recessive hypophosphatemia—a rare genetic dis-
order with essentially similar clinical features as those seen in
the patients with oncogenic osteomalacia, X-linked hypophos-
rickets.8,9Recent studies using wild-type and autosomal domi-
nant hypophosphatemic rickets mutant proteins have identified
key FGF23-specific receptor-mediated signaling.10,11
FIBROBLAST GROWTH FACTOR-23 SIGNALING
FGF23 exerts its bioactivity on selected target tissues by
interacting with its cognate FGF receptors (FGFRs) in the
presence the cofactor klotho.10–12The klotho gene encodes a
single-pass transmembrane protein with an extracellular
domain consisting of two homologous domains that share
& 2008 International Society of Nephrology
Received 12 February 2008; revised 24 March 2008; accepted 1 April
Correspondence: MS Razzaque, Department of Developmental Biology,
Harvard School of Dental Medicine, Research and Education Building,
Room no. 304, 190 Longwood Avenue, Boston, Massachusetts 02115, USA.
E-mails: firstname.lastname@example.org or email@example.com
sequence homology with the b-glucosidase of bacteria and
plants. Klotho facilitates the binding of FGF23 to FGFR1c,
FGFR3c, and FGFR4.11,12FGFRs contain a signal-transducing
extracellular ligand-binding domain and an intracellular
tyrosine kinase domain. The restricted expression of klotho
determines the tissue specificity of FGF23 function.12,13
Klotho is mostly expressed in the renal distal tubular
epithelial cells, the parathyroid gland, and the pituitary
FGF23, in the presence of klotho, can activate downstream
signaling molecules, as determined by activation or phos-
phorylation of FGFR substrate-2a, extracellular signal-
regulated kinase, and early growth response element-1.10,11
Only in the presence of klotho, cells exposed to FGF23
underwent extracellular signal-regulated kinase phosphoryla-
tion and increased the expression of early growth response
element-1 protein. Klotho also enhances FGF23 binding to its
receptor because FGF23 has a greater affinity to the
Klotho–FGFR complex than to the FGFR alone, underscoring
the important role of klotho as a cofactor in the FGF23–FGFR
interaction and subsequent signaling.11Our understanding of
FGF23 and its receptor interactions, along with the down-
stream signaling events, helps us focus on its biological
functions. Recent genetic studies by generating Fgf23- and
klotho-ablated mice, have shown that altered mineral ion
metabolism in the mutant mice is associated with extensive
vascular and soft tissue calcification.15–17
Vascular calcification is a complex, regulated process that
involves themolecular interplay between
stimulators and inhibitors. Although numerous individual
molecules and/or factors have been identified as stimulators
of calcification, including inorganic phosphate, calcium,
sodium phosphate co-transporters, Runx2, tissue nonspecific
alkaline phosphase (TNAP), glucose, acetylated LDL, tumor-
necrosis factor-a, and bone morphogenetic protein-2,18–20
their exact mechanism to induce vascular calcification and
their interaction with the calcification inhibitors is not yet
Recent studies have shed some light on vascular calcifica-
tion and how a disrupted balance between calcification-
inhibiting and -promoting factors can lead to ectopic
calcification. As mentioned, there are several key factors that
have been shown to directly regulate the induction and
progression of vascular calcification; these include but are not
limited to circulating factors (eg, phosphate, calcium,
pyrophosphate, and parathyroid hormone) and their signal-
ing components, matrix molecules (eg, matrix Gla protein;
MGP), and catalyzing enzymes (eg, TNAP).
Serum phosphate and calcium levels are important
determinants of vascular calcification, as inadequate regula-
tion of these minerals can lead to spontaneous deposition of
calcium phosphate in the blood vessels and soft tissues.
Hyperphosphatemia in dialysis patients correlates with
vascular calcification, and effective phosphate control with
noncalcium phosphate binders is correlated with attenuated
progression of vascular calcification in these patients.21In
addition, in vitro studies have shown that smooth muscle
cells grown in the presence of elevated inorganic phosphorus
undergo a dramatic phenotypic change characterized by the
downregulation of smooth muscle cell lineage genes and the
upregulation of the osteochondrogenic lineage genes.22
Similar to phosphorus, a positive calcium balance is linked
to vascular calcification in humans.23In vitro, calcium
promotes mineralization in vascular smooth muscle cells,
and the calcium-induced mineralization upregulates the
expression of the major sodium-dependent phosphate co-
transporters in these cells.24
Inorganic pyrophosphate inhibits vascular calcification by
through its biophysical chelator-like role, as well as stabilizing
the aortic phenotype by acting as a paracrine regulator.19
Reduced plasma pyrophosphate levels are reported in
hemodialysis patients and are exacerbated as a result of
pyrophosphate clearance.25It is therefore likely that restoring
pyrophosphate levels may help in limiting vascular calcifica-
tion. Another factor, TNAP, an enzyme produced in several
tissues including bones, serves as a functional phenotypic
marker of osteoblasts and is often used as a molecular marker
for vascular calcification. Because pyrophosphate is a
substrate for TNAP and phosphorus is the product of its
catalytic activity, one can theoretically anticipate that
upregulated TNAP expression acts as a precursor to vascular
calcification.26Parathyroid hormone can also influence
vascular calcification. Uncontrolled secretion of parathyroid
hormone can release excessive amounts of calcium from
bone, which can precipitate as calcifying foci in blood vessels
and soft tissues.27
Bone morphogenetic protein-2 plays a role in calcification
by exerting osteogenic effects on blood vessels and soft
tissues.28Studies have shown a positive correlation between
bone morphogenetic protein-2 and vascular calcification.
Furthermore, matrix proteins, like MGP can inhibit vascular
calcification. A positive correlation exists between the local
expression of MGP and calcification in arteries. In MGP
knockout mice and human Keutel syndrome, MGP defi-
ciency is associated with ectopic calcification.29MGP is able
to control vascular calcification partly through its Gla
residues, which have a calcium/hydroxy apatite-chelating
Vascular calcification is histologically divided into four
main types: (1) atherosclerotic intimal calcification, (2)
medial artery calcification (Monckeberg sclerosis), (3)
cardiac valve calcification, and (4) arteriole calcification in
the form of calciphylaxis. Although systemic factors have
great importance in inducing calcification, the interplay
between the resident cells of the vasculature usually
determines the extent of the damage; cross talks and
phenotypic alteration of endothelial cells, smooth muscle
cells, pericytes, and perhaps mesenchymal stem cells, in
response to systemic dysregulation of mineral balance can
F Memon et al.: Fgf23, klotho, and calcification
significantly influence the calcification process. In general,
there are significant similarities between skeletal mineraliza-
tion, and vascular and soft tissue calcification.28The reader is
referred to recent reviews for an in-depth overview of the
general aspects of bone and vascular calcification.18,28The
purpose of this review is to briefly discuss the potential effects
of FGF23–klotho activity on the development of vascular and
soft tissue calcification.
DOES FGF23–KLOTHO ACTIVITY INFLUENCE CALCIFICATION?
Both human and animal studies have shown that reduced
FGF23 or klotho activities are closely associated with vascular
and soft tissue calcification.
Extensive vascular and soft tissue calcification is observed in
Fgf23 knockout mice by 6 weeks of age; small and medium
sized arteries and the proximal tubules in the kidneys are the
most extensively affected sites, in addition to the aorta.
Interestingly, the expression of the sodium phosphate co-
transporter, NaPi2a of the proximal tubular epithelial cells is
also upregulated in Fgf23 knockout mice.1Increased tubular
sodium phosphate co-transporter expression (Figure 1) in
these mice may translocate extracellular phosphate within the
cells to facilitate calcification. In addition to kidney and
blood vessels (Figure 2), Fgf23 knockout mice also exhibit
widespread soft tissue calcification in the lungs, skeletal
muscle, skin, urinary bladder, testes, and cardiac muscle.
Vascular and soft tissue calcification appear as early as
6 weeks postnatally and progress with age in Fgf23 knockout
mice.15,16Such widespread calcification in Fgf23 knockout
mice is associated with osteopenia. Autoradiographic studies
of both fore and hind limbs show that the bone mineral
density (BMD) is strikingly reduced in Fgf23 knockout mice,
compared with their control littermates.1
despite reduced BMD, the total body mineral content in
Fgf23 knockout mice is higher due to their extensive vascular
and soft tissue calcification.1,15The Fgf23 knockout mouse
phenotype has clinical relevance, as human studies have also
shown an association between reduced BMD and vascular
calcification;30low BMD is suggested to independently
predict coronary artery disease in women, with a higher
odds ratio than traditional risk factors.31Lower BMD, yet
higher body mineral content in Fgf23 knockout mice,
therefore, provides a unique model to study molecular
regulation of osteoporosis and vascular calcification.1,15
Similar to the Fgf23 knockout animals, mice homozygous
for the hypomorphic alleles of the klotho gene show increased
expression of NaPi2a and NaPi2c co-transporters in the
proximal tubular epithelial cells (Figure 1). Furthermore,
extensive calcification in both vascular and soft tissues,
including lungs, skin, testis, and heart is noted in klotho-
ablated mice. Taking into consideration the phenotypes
of both Fgf23- and klotho-ablated mice, it seems likely that
in vivo dysregulation of the FGF23–klotho axis can lead
to vascular calcification, possibly by affecting mineral
ion metabolism.4,32–34Needless to mention that extensive
vascular and soft tissue calcification in both Fgf23- and
klotho-ablated mice is associated with severe hyperphos-
phatemia, and increased serum level of 1,25 hydroxyvitamin
D.15–17The experimental relevance of both Fgf23- and klotho-
ablated mice has significantly increased due to the fact that
mutations in either human FGF23 or Klotho genes are also
associated with ectopic calcification.
In accord with the animal studies, human diseases associated
with inactivating mutations in either FGF23 or Klotho gene
Figure 1|Expression of NaPi2a. Immunostaining of NaPi2a
protein in kidneys obtained from control (a), Fgf23?/?(b), and
klotho?/?(c) mice. An increased expression of NaPi2a protein
is detected in Fgf23?/?and klotho?/?mice, compared with
wild-type mice. Please note that NaPi2a protein is exclusively
present in the luminal side of the proximal tubular epithelial cells.
Figure 2|Soft tissue and vascular calcification in Fgf23?/?
mice. von Kossa staining on paraffin sections of the kidney
(a, b) and lung (c, d), showing widespread renal (b) and
pulmonary (d) calcifications in Fgf23?/?mice. No such calcification
is noted in the wild-type littermates (a, c). Arrows depict
the calcified vessels in the kidney and lung of the Fgf23?/?
mice (original magnification: kidney, ?20; lung, ?10).
F Memon et al.: Fgf23, klotho, and calcification
express severe ectopic calcification. For instance, familial
tumoral calcinosis is an autosomal recessive disorder
characterized by hyperphosphatemia and ectopic calcifica-
tion; and is associated with diaphysitis, hyperostosis,
arterial aneurysms, dental abnormalities, and angioid streaks
of the retina. Genetic studies have shown evidence that
missense mutations in the human FGF23 gene or GALNT3
Mutations in GALNT3 prevent its ability to selectively
O-glycosylate a furin-like convertase recognition sequence
in FGF23, thus preventing the proteolytic processing of
FGF23 and the secretion of intact FGF23 protein.36Hence,
mutations in either FGF23 or GALNT3 genes reduce FGF23
activities, which lead to hyperphosphatemia and eventually
to tumoral calcinosis in patients with familial tumoral
Klotho is a recently identified cofactor in FGF23 signaling.
Experimental studies have demonstrated convincingly that
FGF23, in the absence of klotho, cannot exert its bioactivities.
For instance, despite extremely high serum levels of Fgf23
(about 2000-fold higher) in klotho-ablated mice, Fgf23 is
unable to exert its phosphaturic effects in these mice.12The
lack of phosphaturic activity despite extremely high levels of
Fgf23 in klotho-ablated mice signifies that Fgf23 is incapable
to perform its physiological functions in the absence of
klotho.32Recently, a point mutation in the human Klotho
gene was reported in a 13-year-old patient with severe
vascular and soft tissue calcification despite significantly high
serum level of FGF23. Lack of function of the Klotho gene
in this patient can attenuate the ability of FGF23 to exert
its phosphate-lowering effects, which can eventually lead to
the severe vascular and soft tissue calcifications.37
CAN FGF23 SUPPRESS CALCIFICATION?
Because reduced FGF23 activity is associated with vascular
and soft tissue calcification in both experimental and human
studies, the clinically relevant question would be that whether
FGF23 has any calcification inhibitory effects. Current
observations suggest that the manipulation of FGF23 activity
can delay calcification through the lowering of serum calcium
and phosphate levels. Also, Shimada et al.38demonstrated
that FGF23 can suppress the renal expression of 1a-hydroxy-
lase, the rate-limiting enzyme that converts the inactive
vitamin D metabolite into its active form. It is possible that
FGF23 can reduce calcification by inhibiting vitamin D
activity. Inaba et al.39recently reported that FGF23 is an
independent factor that is negatively associated with hand
artery, but not aortic calcification in hemodialysis patients,
and proposed plasma FGF23 levels as a reliable marker for
medial peripheral artery calcification in these patients.
Nevertheless, extensive cardiovascular calcification is the
leading cause of death in chronic kidney disease patients
undergoing dialysis, despite their significantly high serum
FGF23 levels.40–42Variability in the degree of failing kidneys
can account for this apparent contradiction: diminishing
renal function interferes to various extents with the ability of
FGF23 to exert its inhibitory effects due to potential defects
in klotho and/or FGFR expression, leading to both elevated
serum FGF23 levels and vascular calcification. Finally, a
recent study on subjects with normal kidney function found
no correlation between serum intact FGF23 and/or fetuin-A
levels, and coronary artery score.43These findings suggest
that under normal renal function, where the kidneys are
effectively maintaining a normal phosphate balance, FGF23 is
not a suitable marker for coronary artery calcification.
Further studies are needed to better understand the role of
FGF23 in vascular and soft tissue calcification under various
The recent understanding of the systemic regulation of
mineral ion homeostasis and vitamin D metabolism by
FGF23–klotho signaling leads us to revisit the mechanistic
aspect of calcification.44–47Whether the FGF23/klotho can
directly inhibit calcification or whether the effect is indirect
due to reduced availability of calcification promoting mineral
FGF23–klotho activity can delay the process of calcification
by negatively impacting the serum phosphate balance. Further
studies will determine if the pharmacological manipulation
of FGF23 activity can be beneficial in fine-tuning existing
treatments of vascular and/or soft tissue calcification.48Such
studies will also expand our understanding of the funda-
mental aspects of mineral ion metabolism under physiological
and pathological conditions, including calcification.
All the authors declared no competing interests.
The original research works that are cited in this paper are,
in part, supported by the grants (R01-073944 to BL) and
(R01-077276 to MSR) provided by NIH (NIDDK). Fahad Memon
is a sophomore at Boston University (Boston, MA, USA) and
majoring in Biomedical Engineering.
1. Sitara D, Razzaque MS, St-Arnaud R et al. Genetic ablation of vitamin D
activation pathway reverses biochemical and skeletal anomalies in
Fgf-23-null animals. Am J Pathol 2006; 169: 2161–2170.
2. Liu S, Zhou J, Tang W et al. Pathogenic role of Fgf23 in Hyp mice.
Am J Physiol Endocrinol Metab 2006; 291: E38–E49.
3.Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis
and skeletal mineralization. Am J Physiol Endocrinol Metab 2003; 285:
4.Razzaque MS, Lanske B. The emerging role of the fibroblast growth
factor-23–klotho axis in renal regulation of phosphate homeostasis.
J Endocrinol 2007; 194: 1–10.
5.ADHR Consortium. Autosomal dominant hypophosphataemic rickets is
associated with mutations in FGF23. The ADHR Consortium. Nat Genet
2000; 26: 345–348.
6.Shimada T, Mizutani S, Muto T et al. Cloning and characterization of
FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl
Acad Sci USA 2001; 98: 6500–6505.
7.Jonsson KB, Zahradnik R, Larsson T et al. Fibroblast growth factor 23 in
oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med
2003; 348: 1656–1663.
F Memon et al.: Fgf23, klotho, and calcification
8.Feng JQ, Ward LM, Liu S et al. Loss of DMP1 causes rickets and Download full-text
osteomalacia and identifies a role for osteocytes in mineral metabolism.
Nat Genet 2006; 38: 1310–1315.
Lorenz-Depiereux B, Bastepe M, Benet-Pages A et al. DMP1 mutations
in autosomal recessive hypophosphatemia implicate a bone matrix
protein in the regulation of phosphate homeostasis. Nat Genet 2006; 38:
Goetz R, Beenken A, Ibrahimi OA et al. Molecular insights into the
klotho-dependent, endocrine mode of action of fibroblast growth factor
19 subfamily members. Mol Cell Biol 2007; 27: 3417–3428.
Kurosu H, Ogawa Y, Miyoshi M et al. Regulation of fibroblast growth
factor-23 signaling by klotho. J Biol Chem 2006; 281: 6120–6123.
Urakawa I, Yamazaki Y, Shimada T et al. Klotho converts canonical
FGF receptor into a specific receptor for FGF23. Nature 2006; 444:
Torres PU, Prie D, Molina-Bletry V et al. Klotho: an antiaging protein
involved in mineral and vitamin D metabolism. Kidney Int 2007; 71:
Nabeshima Y. Toward a better understanding of Klotho. Sci Aging
Knowledge Environ 2006; 2006: pe11.
Razzaque MS, Sitara D, Taguchi T et al. Premature ageing-like phenotype
in fibroblast growth factor 23 null mice is a vitamin-D mediated process.
FASEB J 2006; 20: 720–722.
Razzaque MS, Lanske B. Hypervitaminosis D and premature aging: lessons
learned from Fgf23 and Klotho mutant mice. Trends Mol Med 2006; 12:
Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho
gene leads to a syndrome resembling ageing. Nature 1997; 390: 45–51.
El-Abbadi M, Giachelli CM. Mechanisms of vascular calcification.
Adv Chronic Kidney Dis 2007; 14: 54–66.
Towler DA. Inorganic pyrophosphate: a paracrine regulator of vascular
calcification and smooth muscle phenotype. Arterioscler Thromb Vasc Biol
2005; 25: 651–654.
El-Abbadi M, Giachelli CM. Arteriosclerosis, calcium phosphate deposition
and cardiovascular disease in uremia: current concepts at the bench.
Curr Opin Nephrol Hypertens 2005; 14: 519–524.
Raggi P, Ali O. Phosphorus restriction and control of coronary calcification
as assessed by electron beam tomography. Curr Opin Nephrol Hypertens
2002; 11: 391–395.
Steitz SA, Speer MY, Curinga G et al. Smooth muscle cell phenotypic
transition associated with calcification: upregulation of Cbfa1 and
downregulation of smooth muscle lineage markers. Circ Res 2001; 89:
Braun J, Asmus HG, Holzer H et al. Long-term comparison of a calcium-
free phosphate binder and calcium carbonate—phosphorus metabolism
and cardiovascular calcification. Clin Nephrol 2004; 62: 104–115.
Yang H, Curinga G, Giachelli CM. Elevated extracellular calcium levels
induce smooth muscle cell matrix mineralization in vitro. Kidney Int 2004;
Lomashvili KA, Khawandi W, O’Neill WC. Reduced plasma pyrophosphate
levels in hemodialysis patients. J Am Soc Nephrol 2005; 16: 2495–2500.
Hessle L, Johnson KA, Anderson HC et al. Tissue-nonspecific alkaline
phosphatase and plasma cell membrane glycoprotein-1 are central
antagonistic regulators of bone mineralization. Proc Natl Acad Sci USA
2002; 99: 9445–9449.
Poole KE, Reeve J. Parathyroid hormone—a bone anabolic and catabolic
agent. Curr Opin Pharmacol 2005; 5: 612–617.
28.Towler DA, Shao JS, Cheng SL et al. Osteogenic regulation of vascular
calcification. Ann NY Acad Sci 2006; 1068: 327–333.
Hur DJ, Raymond GV, Kahler SG et al. A novel MGP mutation in a
consanguineous family: review of the clinical and molecular
characteristics of Keutel syndrome. Am J Med Genet A 2005; 135: 36–40.
Reddy J, Bilezikian JP, Smith SJ et al. Reduced bone mineral density is
associated with breast arterial calcification. J Clin Endocrinol Metab 2008;
Marcovitz PA, Tran HH, Franklin BA et al. Usefulness of bone mineral
density to predict significant coronary artery disease. Am J Cardiol 2005;
Lanske B, Razzaque MS. Premature aging in klotho mutant mice: cause or
consequence? Ageing Res Rev 2007; 6: 73–79.
Razzaque MS, St-Arnaud R, Taguchi T et al. FGF-23, vitamin D and
calcification: the unholy triad. Nephrol Dial Transplant 2005; 20: 2032–2035.
Lanske B, Razzaque MS. Mineral metabolism and aging: the fibroblast
growth factor 23 enigma. Curr Opin Nephrol Hypertens 2007; 16: 311–318.
Topaz O, Shurman DL, Bergman R et al. Mutations in GALNT3, encoding
a protein involved in O-linked glycosylation, cause familial tumoral
calcinosis. Nat Genet 2004; 36: 579–581.
Kato K, Jeanneau C, Tarp MA et al. Polypeptide GalNAc-transferase T3 and
familial tumoral calcinosis. Secretion of fibroblast growth factor 23
requires O-glycosylation. J Biol Chem 2006; 281: 18370–18377.
Ichikawa S, Imel EA, Kreiter ML et al. A homozygous missense mutation in
human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007; 117:
Shimada T, Hasegawa H, Yamazaki Y et al. FGF-23 is a potent regulator of
vitamin D metabolism and phosphate homeostasis. J Bone Miner Res
2004; 19: 429–435.
Inaba M, Okuno S, Imanishi Y et al. Role of fibroblast growth factor-23
in peripheral vascular calcification in non-diabetic and diabetic
hemodialysis patients. Osteoporos Int 2006; 17: 1506–1513.
Stompor T. An overview of the pathophysiology of vascular calcification
in chronic kidney disease. Perit Dial Int 2007; 27(Suppl 2): S215–S222.
Cozzolino M, Mazzaferro S, Pugliese F et al. Vascular calcification and
uremia: what do we know? Am J Nephrol 2007; 28: 339–346.
DeLoach SS, Berns JS. Arterial stiffness and vascular calcification in dialysis
patients: new measures of cardiovascular risk. Semin Dial 2007; 20:
Roos M, Lutz J, Salmhofer H et al. Relation between plasma fibroblast
growth factor-23, serum fetuin-A levels and coronary artery calcification
evaluated by multislice computed tomography in patients with normal
kidney function. Clin Endocrinol (Oxf) 2008; 68: 660–665.
Razzaque MS. Klotho and Na+,K+-ATPase activity: solving the calcium
metabolism dilemma? Nephrol Dial Transplant 2008; 23: 459–461.
Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high
concentrations of 1,25-dihydroxyvitamin D in homozygous klotho
mutant mice by increased expression of renal 1alpha-hydroxylase gene.
Endocrinology 2002; 143: 683–689.
Miyamoto K, Ito M, Tatsumi S et al. New aspect of renal phosphate
reabsorption: the type IIc sodium-dependent phosphate transporter.
Am J Nephrol 2007; 27: 503–515.
Lanske B, Razzaque MS. Vitamin D and aging: old concepts and new
insights. J Nutr Biochem 2007; 18: 771–777.
Razzaque MS. Can fibroblast growth factor 23 fine-tune therapies for
diseases of abnormal mineral ion metabolism? Nat Clin Pract Endocrinol
Metab 2007; 3: 788–789.
F Memon et al.: Fgf23, klotho, and calcification