translational nephrology
org
Vitamin D: a pleiotropic hormone
Annemieke Verstuyf1, Geert Carmeliet1, Roger Bouillon1 and Chantal Mathieu1
1
Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
The secosteroid hormone 1a,25-dihydroxyvitamin D3
(1,25(OH)2D3) is the natural ligand for the vitamin D receptor,
a member of the nuclear receptor superfamily. Upon binding
of the ligand, the vitamin D receptor heterodimerizes with
the retinoid X receptor and binds to vitamin D response
elements in the promoter region of target genes to induce/
repress their expression. The target genes that have been
identified so far are heterogeneous in nature and reflect the
great spectrum of biological activities of 1,25(OH)2D3. Within
the last two decades, the receptor has been shown to be
present not only in classical target tissues such as bone,
kidney, and intestine, but also in many other nonclassical
tissues, for example, in the immune system (T and B cells,
macrophages, and monocytes), in the reproductive system
(uterus, testis, ovary, prostate, placenta, and mammary
glands), in the endocrine system (pancreas, pituitary, thyroid,
and adrenal cortex), in muscles (skeletal, smooth, and heart
muscles), and in brain, skin, and liver. Besides the almost
universal presence of vitamin D receptors, different cell types
(for example, keratinocytes, monocytes, bone, placenta) are
capable of metabolizing 25-hydroxyvitamin D3 to
1,25(OH)2D3 by the enzyme 25(OH)D3-1a-hydroxylase,
encoded by CYP27B1. The combined presence of CYP27B1
and the specific receptor in several tissues introduced the
idea of a paracrine/autocrine role for 1,25(OH)2D3. Moreover,
it has been demonstrated that 1,25(OH)2D3 can induce
differentiation and inhibit proliferation of normal and
malignant cells. Moreover, vitamin D deficiency is associated
with an increased risk for nearly all major human diseases
such as cancer, autoimmune diseases, cardiovascular, and
metabolic diseases. In addition to the treatment of bone
disorders with 1,25(OH)2D3, these newly discovered functions
open perspectives for the use of 1,25(OH)2D3 as an immune
modulator (for example, for the treatment of autoimmune
diseases or prevention of graft rejection), inhibitor of cell
proliferation, and inducer of cell differentiation (cancer).
Kidney International (2010) 78, 140–145; doi:10.1038/ki.2010.17;
published online 24 February 2010
KEYWORDS: activated vitamin D; bone; calcium; cancer; immunology
Correspondence: Roger Bouillon, Laboratory of Experimental Medicine and
Endocrinology, Katholieke Universiteit Leuven, Herestraat 49 – O&N1 bus 902,
B-3000 Leuven, Belgium. E-mail: roger.bouillon@med.kuleuven.be
Received 15 July 2009; revised 10 December 2009; accepted 28
December 2009; published online 24 February 2010
140
http://www.kidney-international.
& 2010 International Society of Nephrology
VITAMIN D IN BONE AND CALCIUM HOMEOSTASIS
1a,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a major
calcitropic hormone with as primary purpose to keep the
plasma Ca2 þ concentration within narrow limits. The renal
production of 1,25(OH)2D3 is therefore tightly regulated
by two hormones. First, hypocalcemia induces the secretion
of parathyroid hormone (PTH) by the parathyroid gland.
PTH targets the kidney to decrease Ca2 þ excretion, inhibit
phosphate reabsorption, and stimulate 1,25(OH)2D3 produc-
tion. 1,25(OH)2D3 will then increase active Ca2 þ and
phosphate transport in the small intestine and stimulate
Ca2 þ reabsorption in the kidney. In concert with the effects
of PTH on bone, 1,25(OH)2D3 action also enhances Ca2 þ
exchange from bone and the cooperation of these pathways
restores serum Ca2 þ levels to normal. Second, 1,25(OH)2D3
stimulates the secretion of FGF23 by the osteocytes. FGF23 is
the major phosphaturic hormone inhibiting renal phosphate
reabsorption (by the specific transporter NaPiT2a) and
decreasing the renal production of 1,25(OH)2D3. In addition,
1,25(OH)2D3 and phosphate stimulate and FGF23 inhibits
PTH production creating a true phosphate feedback loop.
The analysis of transgenic mouse models permitted to
elucidate the molecular pathway involved and to delineate
direct versus indirect action of 1,25(OH)2D3 on the different
target tissues.
Genetic deficiencies in 1,25(OH)2D3 signaling by loss
of CYP27B1 or vitamin D receptor (VDR) result in hypo-
calcemia, hyperparathyroidism, hypophoshatemia, rickets,
and osteomalacia. These effects, however, are only observed
after weaning, when dietary calcium content decreases. The
phenotype can largely be corrected by administration of
a high calcium diet that bypasses active, 1,25(OH)2D3-
mediated, Ca2 þ absorption.1 The action of 1,25(OH)2D3 to
promote intestinal transcellular Ca2 þ transport is, therefore,
mainly required when dietary calcium content is low to
normal. The importance of VDR signaling in the intestine
is underscored by the observation that reintroducing
VDR specifically in the intestine of VDR null mice rescued
the hypocalcemia and the bone phenotype.2,3 The proteins
involved in this active intestinal Ca2 þ transport remain,
however, poorly defined.
Gene expression analysis suggested that the Ca2 þ channel
TRPV6 (transient receptor potential vanilloid type 6),
mediating Ca2 þ entry across the luminal membrane, and
calbindin D9k, facilitating cytoplasmic Ca2 þ transfer toward
the basolateral membrane, are the main mediators of
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A Verstuyf et al.: Vitamin D: a pleiotropic hormone
1,25(OH)2D3-induced intestinal Ca2 þ absorption.4 Surpris-
ingly, inactivation of TRPV6 and calbindin D9k does not
impair intestinal Ca2 þ absorption when dietary calcium
intake is normal, indicating the contribution of compensa-
tory proteins. Nevertheless, TRPV6 becomes critical for Ca2 þ
absorption when dietary calcium intake is low, as evidenced
by the impaired intestinal Ca2 þ absorption in TRPV6 null
mice on a low calcium diet.5,6 A possible explanation for the
lack of effect is that 1,25(OH)2D3 action not only affects
transcellular but also paracellular Ca2 þ transport. Indeed,
1,25(OH)2D3 may regulate tight junction permeability in the
intestine by modifying the expression of several tight junc-
tion proteins, including claudin-2 and claudin-12 and hereby
promoting Ca2 þ absorption.7 As mentioned, 1,25(OH)2D3
promotes renal Ca2 þ reabsorption that correlates with
increased expression of TRPV5 and calbindin D9k. In contrast
to the limited contribution of TRPV6 to intestinal Ca2 þ
absorption, TRPV5 is definitely critical for renal Ca2 þ
reabsorption. Indeed, TRPV5 null mice display a profound
Ca2 þ wasting with compensatory increased intestinal Ca2 þ
absorption, likely due to high 1,25(OH)2D3 serum levels, and
normocalcemia as a result.8
If the major action of 1,25(OH)2D3 is to keep serum Ca2 þ
levels within restricted limits, the question can be raised
whether the sole action of 1,25(OH)2D3 on bone is to
diminish changes in the serum Ca2 þ concentrations by
increased bone resorption or whether there is also a direct
(positive) effect of 1,25(OH)2D3 on bone homeostasis.
Indeed, 1,25(OH)2D3 can stimulate bone resorption by
increasing the expression of osteoclastogenic factors (for
example, receptor activator of nuclear factor kB ligand) in
osteoblasts. There is, however, increasing evidence that
1,25(OH)2D3-mediated signaling has a defined, albeit non-
essential function in regulating the activity of chondrocytes
and osteoblasts during endochondral bone formation and
bone homeostasis. A first indication is the observation that
aberrant growth plate development in VDR-deficient mice
appears before the onset of hypocalcemia and that a high
calcium diet corrected all aspects of the phenotype of
CYP27B1-deficient mice, except long bone growth.1 Genetic
evidence is provided by the phenotype of mice lacking VDR
expression in chondrocytes.9 These mice display a normal
growth plate, but develop a transient phenotype of increased
bone volume postnatally, likely due to decreased expression
of the angiogenic factor vascular endothelial growth factor
and the osteoclastogenic factor receptor activator of nuclear
factor kB ligand in chondrocytes. In addition, VDR signaling
in chondrocytes increases, by an unidentified mechanism, the
expression of the phosphaturic factor FGF23 in osteoblasts.
FGF23 signals to the kidney where it reduces phosphate
reabsorption and CYP27B1 activity. Although not completely
identical, most of these effects are also observed when
CYP27B1 is deleted in chondrocytes, supporting a physio-
logical function for an autocrine/paracrine vitamin D
pathway in developing chondrocytes.10 These data indicate
that 1,25(OH)2D3-mediated signaling in chondrocytes is
Kidney International (2010) 78, 140–145
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necessary for timely vascular invasion and osteoclastogenesis
during bone growth and that this pathway is required for
proper endocrine action of bone in phosphate homeostasis.
The function of VDR in osteoblasts seems to be modu-
lated as a function of the differentiation stage of the cells.
Indeed, VDR activation in pre-osteoblasts suppresses bone
formation as calvarial osteoblasts from VDR null mice
displayed enhanced osteogenesis in vitro,11 whereas the
expression of a VDR transgene in mature osteoblasts results
in increased bone mass.12
Selective deletion of VDR from the parathyroid glands
causes a doubling of PTH levels and increased bone turnover
without overall negative effects on bone.13 This indicates that
the calcium-sensing parathyroid gland is a direct target for
vitamin D action and thus may contribute to the secondary
hyperparathyroidism in chronic renal failure.
Taken together, the major function of 1,25(OH)2D3/VDR
signaling is to guarantee normal serum Ca2 þ levels, but this
pathway also directly affects the homeostasis and endocrine
function of bone.
VITAMIN D AND CANCER
Several large-scale epidemiological studies have shown an
inverse correlation between exposure to sunlight (the major
source of vitamin D) or vitamin D intake and risk of
colorectal, breast, and prostate cancer. However, the fact that
people in sunny Southern Europe have a lower vitamin D
status than those in Northern Europe indicates that sun
exposure and diet are not such good indicators for the
vitamin D status.14 Moreover, the vitamin D content in food
is highly variable. Therefore, prospective studies using serum
25(OH)D3 levels to assess vitamin D status are more accurate
to study the relationship between 25(OH)D3 status and
cancer incidence. A recent meta-analysis of the association
between serum 25(OH)D3 and colorectal cancer risk15
supports the conclusion that lower serum 25(OH)D3 levels
are inversely associated with colorectal cancer and confirmed
another meta-analysis,16 which reported that a 51% lower
incidence of colorectal cancer was associated with the highest
serum 25(OH)D3 quintile (82 nmol/l) compared to the
lowest quintile (p30 nmol/l). The association between breast
cancer risk and 25(OH)D3 status has been studied among
others in the United States17 as well as in Europe.18 The UK
study showed that women with 25(OH)D3 levels o50 nmol/l
have an odds ratio of 3.54 for breast cancer risk compared
with women with levels 450 nmol/l. However, other
epidemiological studies failed to show an inverse correlation
between 25(OH)D3 circulating levels and breast cancer
incidence. Similarly the association between 25(OH)D3 status
and prostate cancer19 is less clear than for colorectal cancer.
Moreover, the association between overall cancer outcome
and 25(OH)D3 remains ambiguous. In the large WHI,
combined treatment of vitamin D3 (400 IU per day) and
calcium did not decrease colon cancer risk,20 whereas in a
much smaller randomized control trial 1100 IU per day of
vitamin D3 along with calcium decreased the overall cancer
141
translational nephrology
risk.21 Therefore, additional intervention studies are needed
to investigate the effect of vitamin D supplementation alone
on cancer risk.
The conversion from 25(OH)D3 to 1,25(OH)2D3 by
CYP27B1 is not restricted to the kidney but can also take
place in other cell types such as keratinocytes, immune, or
bone cells but also in breast, prostate, or colon cancer cells,
raising the possibility that locally synthesized 1,25(OH)2D3
behaves in an autocrine or paracrine way. Indeed, the kidney
tubular cell is the only normal cell that can export its
1,25(OH)2D3. The same CYP27B1 enzyme can, however, be
activated by totally different stimuli (for example, cytokines
stimulating monocyte CYP27B1) and generate 1,25(OH)2D3
with mainly autocrine and paracrine activity. Therefore,
much like T4-T3 for the thyroid system, 25(OH)D3 can be a
precursor for local action. However, the relative function of
local versus systemic production of 1,25(OH)2D3 is yet
poorly defined.
1,25(OH)2D3 exerts its biological effects by binding to the
VDR and after dimerization with retinoid X receptor, the
complex binds to vitamin D responsive elements in the
promoter region of target genes, recruits coregulators and the
transcriptional preinitiation complex to initiate target gene
transcription. During the last decades it became clear that
supraphysiological doses of 1,25(OH)2D3 have potent
growth-inhibitory and pro-differentiating effects on a large
variety of cell types. Moreover, a physiological function for
1,25(OH)2D3 in the regulation of normal cell growth is
suggested by the finding that in VDR/ mice hyperproli-
feration in the colon and mammary gland is present.
Although these mice do not develop cancer spontaneously,
they are predisposed to cancer when challenged with
carcinogenic agents.1 1,25(OH)2D3 inhibits cell growth by
hampering the transition from the G1 to the S phase of the
cell cycle (Figure 1). 1,25(OH)2D3 accumulates cells in the
G1 phase by targeting cell-cycle regulators in a direct or
indirect way. As such the cyclin-dependent kinase inhibitor
p21(waf1/cip1) is directly activated by 1,25(OH)2D3 through a
vitamin D responsive element in its promoter region
(Figure 1). In addition to an increase of cyclin-dependent
kinase inhibitor p27(kip1) protein levels due to posttransla-
tional modifications, it has been recently shown that
1,25(OH)2D3-induced repression of the miR181 family contri-
butes to the accumulation of p27(kip1)22 by 1,25(OH)2D3.
1,25(OH)2D3 also decreases cyclin D1 and cyclin E expression
and the activity of complexes between cyclins and cyclin-
dependent kinases (Figure 1). As a result 1,25(OH)2D3
influences the phosphorylation status of the retinoblastoma
pocket protein family, preventing the release of the E2F
transcription factors 1, 2, 3 and keeps the inhibitory
complexes of E2F4 and E2F5 with p107 and p130 pocket
proteins on the promoter of cell-cycle target genes (Figure 1).23
To identify new key genes that are regulated by 1,25(OH)2D3,
a large number of microarray studies have been performed on
different types of cancer cells. From these studies, it became
clear that not one single gene or one single pathway mediates
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A Verstuyf et al.: Vitamin D: a pleiotropic hormone
1,25(OH)2D3
p15 p19 p21 p27
Cdk4/6
Cyclin D1,2,3
Cdk2
Cyclin E
Cell cycle
p107/p130 E2F-target
P pRb
genes
pRb P DP E2F4,5
P DP E2F
1,2,3
Figure 1 | 1a,25-Dihydroxyvitamin D3 (1,25(OH)2D3) blocks the
progression of cells from the G1 to the S phase of the cell
cycle. 1,25(OH)2D3 induces the expression of different cyclin-
dependent kinase (Cdk) inhibitors (p15, p19, p21, and p27), which
inhibit the activity of cyclin/Cdk complexes (Cyclin D1, 2, 3/
Cdk4–6; Cyclin E/Cdk2). Reduced cyclin (cyclin D, cyclin E)
expression after treatment with 1,25(OH)2D3 also contributes to a
reduced cyclin/Cdk activity. The pocket proteins retinoblastoma
(pRb), p107, and p130 remain in an underphosphorylated state
because of the reduced cyclin/Cdk activity. E2F4 and E2F5 remain
in association with the hypophosphorylated p107 and p130
pocket proteins and act as transcriptional repressors in quiescent
and early G1 cells. Due to the hypophosphorylated status of pRb,
the transcriptional activators E2Fs1–3 remain bound and are not
able to target the promoter region of cell-cycle genes to initiate
the transition of G1 to S phase. As a result, cells are blocked in the
G1 phase of the cell cycle after treatment with 1,25(OH)2D3 (k,
stimulatory effect; >, inhibitory effect).
the antiproliferative effects of 1,25(OH)2D3 but that multiple
pathways are involved, among which epidermal growth factor,
insulin-like growth factor, transforming growth factor,
prostaglandins, and Wnt-b-catenin signaling cascades.1,24
The variety of target genes identified through these studies
reflect the pleiotropic action of 1,25(OH)2D3 in different
cellular processes next to cell-cycle progression, such as
apoptosis, cellular adhesion, and oxidative stress. The presence
of the VDR in tumors together with the growth-regulatory
effect of 1,25(OH)2D3 opens perspectives for the use of this
compound in cancer prevention and/or treatment.
1,25(OH)2D3 has been evaluated in different dose settings
and in different combinations (dexamethasone, docetaxel,
estramustine, mitoxantrone, and prednisone) in patients with
prostate cancer. These small trials indicated that a high weekly
dose of 1,25(OH)2D3 instead of daily administration was safe
and combination therapies were well tolerated. In the Ascent
phase III clinical trial (Novacea, South San Francisco, CA,
USA) a large cohort of patients (950) with androgen-
independent prostate cancer was treated either with Taxotere
administered every 3 weeks (control arm) or with a weekly
high dose of 1,25(OH)2D3 (DN-101) in combination with
once-weekly Taxotere. Unfortunately, this trial was terminated
earlier than the design of 30 weeks of treatment due to an
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A Verstuyf et al.: Vitamin D: a pleiotropic hormone
unexplained imbalance of deaths between the treatment and
control group of the trial. Worldwide research has focused on
the development of structural analogs of 1,25(OH)2D3 with a
clear dissociation between antiproliferative and calcemic
effects. One of these analogs, TX 522 (Inecalcitol; Hybrigenics,
Paris, France) is currently in phase II in patients with
hormone-refractory prostate cancer. Preliminary results
showed that 27 of the 31 patients treated with Inecalcitol (at
different doses up to 600 mg per day) and Taxotere during 18
weeks showed a decrease in prostate-specific antigen levels of
more than 30% within 3 months of initiation of treatment
without any changes in calcium parameters.25
VITAMIN D AS IMMUNE MODULATOR
Exposure of skin to UVB results in immunosuppression and
part of this effect is mediated through synthesis of vitamin D
and activation to its active form 1,25(OH)2D3 under the
influence of UVB.26 This phenomenon hints toward a
physiological function for vitamin D in immune regulation
and in recent years, an increasing amount of data have
become available to support such a physiological function for
the vitamin D system in immune function, both in defense
and in maintenance of self-tolerance. Receptors for vitamin
D have been described in most cells of the immune system
and many immune cells express the hydroxylase enzymes that
can provide hydroxylation of vitamin D on the 25 and the 1a
site (CYP27A1/CYP2R1 and CYP27B1, respectively).27 Im-
mune cells can thus activate 25(OH)D3 to 1,25(OH)2D3,
providing within the immune system a paracrine presence of
1,25(OH)2D328 (Figure 2).
Secretion of 1,25(OH)2D3 by immune cells is regulated
differently from its secretion by kidney cells, with immune
stimuli, rather than calcemic stimuli regulating levels of
1,25(OH)2D3 in inflammatory foci. A crucial immune
stimulus in the regulation of the final hydroxylation step
(1a-hydroxylation by CYP27B1) is interferon-g. However,
although important, interferon-g is not sufficient by its own,
because other macrophage activators/differentiators, such
as lipopolysaccharide, phorbol myristate acetate, or tumor
necrosis factor-a, need to be present simultaneously to
activate a complex network of signaling pathways, necessary
for CYP27B1 induction. Adding to this, not only TLR4
activation, but also TLR2/1 triggering is able to induce
1a-hydroxylase in human macrophages, paralleled by
induction of an antimicrobial response. Finally, also the
1,25(OH)2D3-metabolizing enzyme, CYP24A1, responsible
for 24-hydroxylation, is expressed by antigen-presenting cells.
1,25(OH)2D3 affects the immune system in many different
ways, but the overall picture is one of enhanced capacity of
innate antibacterial defense and a more tolerogenic profile
toward autoimmune phenomena. The dendritic cell (DC)
and other antigen-presenting cells, such as the Langerhans
cells in skin, are central to the effect of vitamin D, affecting
dramatically the direction in which the immune system is
skewed. Human and animal data indicate that maturation,
differentiation, and function of DCs is affected, with
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Target tissue
IL-12 DC
CD40 MHC II
IL-1
CD80/86
TNF-α Ag
Free radicals TCR CD28
CD40L
Tc Th2
CD4+T
IL-4
1,25(OH)2D3 IL-5
Mφ IL-10
Treg
Th1
N° IFN-γ IL-10
IL-2 TFG-β
Th17
IL-17
Figure 2 | Immunomodulatory effects of 1a,25-
Dihydroxyvitamin D3 (1,25(OH)2D3). 1,25(OH)2D3 inhibits the
expression of costimulatory molecules (CD40, CD80, CD86) and
major histocompatibility complex class II (MHC-II) on the cell
surface of antigen-presenting cells (including dendritic cells, DCs),
and inhibits the production of inflammatory cytokines such as
interleukin-12 (IL-12). By this, 1,25(OH)2D3 indirectly shifts T-cell
polarization from an inflammatory Th1 to a protective Th2 and
regulatory T-cell phenotype (Treg). 1,25(OH)2D3 also directly
modulates T-cell responses, by inhibition of inflammatory Th1 and
Th17 cytokines and upregulation of Th2 cytokines. These
integrated effects of 1,25(OH)2D3 on the immune system might
contribute to the prevention of autoimmune diseases such as
type 1 diabetes.
downregulation of major histocompatibility complex class
II and costimulatory molecules, such as CD40, CD80, and
CD86, resulting in a tolerance-promoting phenotype. The
effect of 1,25(OH)2D3 on DC phenotype and function is
an integrated effect, not fully explained by prevention of
differentiation as indicated by both transcriptional and
translational data.29 Through these DC alterations and effects
on cytokine secretion by the DC (favoring IL10 and
inhibiting IL12), T-cell function is fundamentally affected,
promoting development of Th2 lymphocytes within the
CD4 þ subset, but also affecting CD8 þ CTL development.30
T lymphocytes can also be direct targets for 1,25(OH)2D3,
resulting in inhibition of several cytokines, such as interferon-g
and IL-17, or stimulation of others such as IL-4.1 Importantly,
1,25(OH)2D3 affects the expression of chemokine receptors on
the surface of T lymphocytes and will thus determine the target
tissue where any primed T lymphocytes will migrate to.31 The
integrated effect of 1,25(OH)2D3 on DC and T lymphocytes
provides a unique potential of this substance to generate
regulator cells (Tregs). In different model systems,
1,25(OH)2D3 has been shown to induce Tregs. The nature of
these Tregs differs from system to system, but their presence is
clear and they appear to be stable.32
Finally, another important target cell of 1,25(OH)2D3 is
the monocyte/macrophage, the cell responsible for anti-
bacterial and antiviral defenses. Here 1,25(OH)2D3 is a
crucial factor in promoting the antibacterial defense system
of macrophages, by promoting secretion of antibacterial
products such as cathelicidin.33
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translational nephrology
These immunomodulatory effects of 1,25(OH)2D3 can
clearly be observed in vivo in circumstances of vitamin D
deficiency both in humans and in animal models of human
disease. Decreased antibacterial and antiviral defenses are
obvious in vitamin D deficiency and restoration of the
vitamin D-sufficient state restores immune responses.
Correlations between the existence of vitamin D deficiency
and higher prevalence of autoimmunity have been described
for many diseases and in different populations. Indeed, many
epidemiological studies have shown a clear association
between low vitamin D status and autoimmune diseases,
such as type 1 diabetes,34 multiple sclerosis,35,36 and
inflammatory bowel disease. Preclinical animal models have
confirmed that vitamin D deficiency especially early in life
enhances such autoimmune diseases. Prospective interven-
tion studies with either vitamin D or selective VDR
modulators are, however, needed to evaluate their therapeu-
tic potential.
CARDIOVASCULAR AND METABOLIC ACTIONS
Vitamin D-deficient rats or mice with deletion of VDR or
1a-hydroxylase develop high renin hypertension with
ultimately cardiac hypertrophy. Selective VDR deficiency in
cardiac myocytes can reproduce the effects.37 In normo-
tensive and hypertensive Caucasian, Hispanic, or African
Americans lower serum 25(OH)D levels are associated with
higher blood pressure.38 Moreover, in normotensive and
hypertensive patients blood pressure is inversely correlated
with plasma 1,25(OH)2D and renin concentrations.1 How-
ever, low 25(OH)D levels are also associated with nearly all
aspects of the metabolic syndrome, such as obesity, insulin
resistance, type 2 diabetes. The fat–vitamin D axis is further
underlined by lower fat mass and resistance to diet-induced
obesity in VDR null mice and a negative effect of the major
fat cell hormone, leptin, on renal 1a-hydroxylase activity.
However, there are only very small scale intervention studies
using vitamin D or its active hormone on blood pressure or
other aspects of the metabolic syndrome.39,40
CLINICAL PERSPECTIVES
The major function of 1,25(OH)2D3/VDR signaling is to
control the calcium and bone homeostasis. Data obtained in
animal models of vitamin D deficiency and resistance are
generally perfectly in line with observations in rare patients
with such human diseases. The combined presence of
25(OH)D3-1a-hydroxylase as well as VDR in several non-
classical tissues introduced the concept of a paracrine/
autocrine function for 1,25(OH)2D3 outside the calcium
and bone metabolism. Moreover, the fact that 1,25(OH)2D3
was found to be capable of regulating cell differentiation and
proliferation of normal (immune) cells and malignant cells
created new perspectives for this molecule. The extensive
studies in cells, tissues, and whole animals with modified
vitamin D action have generated clear hypothesis to evaluate
the function of vitamin D (deficiency) on a whole spectrum
of human diseases.
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A poor vitamin D status is linked with all major diseases
causing the majority of human morbidity, such as cancer,
immune diseases, metabolic syndrome, hypertension, and
cardiovascular risk factors. Correction of vitamin D defi-
ciency or insufficiency usually requires vitamin D supple-
mentation as higher exposure to UVB light carries a risk for
skin damage and carcinogenesis and as naturally vitamin
D-rich food is scarce. In Europe, the vitamin D3 is preferred
whereas vitamin D2 is widely added to food or used as
supplement in North America. The natural D3 compound is
probably slightly more potent than vitamin D2 especially
when given intermittently. The optimal daily dosage is highly
debated but most randomized controlled trials used
600–1000 IU of vitamin D3 per day and such therapy was
found to decrease the risk of fractures and falls in the elderly.
The serum 25(OH)D concentration should certainly exceed
20 ng/ml (or 50 nmol/l) and probably even 30 ng/ml
(80 nmol/l) in patients with impaired renal function. As the
mean level of 25(OH)D around the world is only about
20 ng/ml41 and not higher than 30 ng/ml in the US NHANES
IV participants,42 it can be easily assumed that a very large
part of the human population and thus even billions of
people is at least mildly vitamin D deficient.
Patients with chronic renal failure have a greater than
normal risk for bone diseases, cancer, immune disorders,
as well as increased cardiovascular mortality. They also
have impaired production of 1,25(OH)2D3 and frequently
combine this with 25(OH)D3 deficiency. A number of
observational studies have shown that treatment of hemo-
dialysis patients with active vitamin D analogs decreases
(cardiovascular) mortality. The overall contribution of
combined impaired 25(OH)D3–1,25(OH)2D3 status on
morbidity and mortality in patients with chronic renal
failure may be substantial but needs further randomized
control trials.
DISCLOSURE
AV, GC, and CM declared no competing interests. RB received
consultancy fees (Lilly, Indianapolis, IN, USA, Tibotec, Mechelen,
Belgium, BioXell, Segrate, Italy) and lecture fees (Merck & Co.,
Whitehouse Station, NJ, USA, Amgen, Thousand Oaks, CA, USA) and
has intellectual property rights on a university patent on vitamin D
analogs licensed to Hybrigenics, France.
ACKNOWLEDGMENTS
We thank Femke Baeke and Lieve Verlinden for the creation of the
figures and Evelyne van Etten for editorial assitance. CM is a clinical
researcher for the Fund for Scientific Research (FWO-Vlaanderen). The
work in the author’s laboratories was supported by FWO Vlaanderen
(FWO G.0587.09, G.0553.06, G.0552.06), the University of Leuven
(GOA/04/10, EF/05/007), and Belgium Program on Interuniversity
Poles of Attraction (P6/34).
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