From the Second Department of Internal Medicine, Osaka City University
Medical School, Osaka 545, Japan.
Correspondence to Atsushi Shioi, MD, Second Department of Internal Medicine, Osaka City University Medical School, 1-5-7 Asahi-machi, Abeno-ku, Osaka 545, Japan. E-mail as{at}msic.med.osaka-cu.ac.jp
Methods and Results—We investigated the effect of
1,25(OH)2D3 on in vitro calcification by bovine
vascular smooth muscle cells (BVSMCs).
1,25(OH)2D3 dose dependently increased BVSMC
calcification and alkaline phosphatase activity.
1,25(OH)2D3 also decreased secretion of PTHrP
by BVSMCs in a dose-dependent manner and depressed its gene expression.
Furthermore, exogenous PTHrP (fragment 1-34) antagonized the
stimulatory effect of 1,25(OH)2D3 on BVSMCs.
Finally, 1,25(OH)2D3 dose dependently increased
the expression of the osteopontin gene, one of the bone matrix proteins
in BVSMCs, contributing to its stimulatory action on BVSMC
calcification.
Conclusions—These data suggest that
1,25(OH)2D3 exerts a stimulatory effect on
vascular calcification through direct inhibition of the expression of
PTHrP in BVSMCs as an endogenous
inhibitor of vascular calcification. Moreover, the
stimulatory effects of 1,25(OH)2D3 on alkaline
phosphatase activity and osteopontin expression may contribute to its
promoting action in vascular calcification.
Vascular calcification often occurs in women with
osteoporosis.11 12 13 14 Moreover, there is an inverse
relationship between the degree of vascular calcification and bone
mineral content, suggesting that calcium homeostasis is important in
atherosclerotic calcification as well as in
osteoporosis.15 Calcium-regulating hormones such
as parathyroid hormone (PTH), PTH-related peptide (PTHrP), and vitamin
D thus may modulate atherosclerotic calcification. We have demonstrated
that PTH and PTHrP inhibit BVSMC calcification through depression of
ALP activity and that PTHrP secreted from BVSMCs acts as an
endogenous inhibitor of vascular calcification,
suggesting that VSMCs are equipped with an autocrine and/or a paracrine
system that regulates calcium
metabolism.16
1
We hypothesized that
1,25(OH)2D3 may have a
direct impact on the calcium-regulating system of VSMCs, resulting in
deposition of calcium in vascular wall. In this study, we investigated
the effect of 1,25(OH)2D3
on in vitro calcification by BVSMCs and demonstrated that
1,25(OH)2D3 increases
calcium deposition by depressing endogenous PTHrP
expression.
Cell Culture and In Vitro Calcification
Quantification of Calcium Deposition
Measurement of PTHrP
ALP Assay
RNA Isolation and Northern Blot Analysis
Statistics
Because we have demonstrated that PTHrP secreted from BVSMCs acts as an
endogenous inhibitor of vascular
calcification,16 we next examined the effect of
1,25(OH)2D3 on PTHrP
secretion by BVSMCs. PTHrP secretion was decreased in each group in the
presence of ß-GP (calcified condition) compared with its absence
(uncalcified condition) (Figure 3
Finally, we examined the effect of
1,25(OH)2D3 on the
expression of OPN mRNA because we showed that OPN mRNA is expressed
exclusively in calcified BVSMCs10 and that
recombinant OPN peptide dose dependently increases this calcification
(Jono et al, unpublished observation, 1997).
1,25(OH)2D3 dose
dependently increased the expression of OPN gene in BVSMCs, and at
10–7 mol/L, the mRNA level reached 143.7% of
control (Figure 4b
It has been demonstrated that
1,25(OH)2D3 suppresses
PTHrP gene transcription in various types of cells, such as rat
osteosarcoma cell line (ROS 17/2.8), human squamous cell line (NCI
H520), and human
keratinocytes.24 25 26 The PTHrP
gene has an inhibitory vitamin D response element within
its promoter region, which can interact with a vitamin D
receptor/retinoid X-receptor heterodimer.24
Therefore, the inhibitory action of
1,25(OH)2D3 on PTHrP gene
expression in BVSMCs, as shown in this study, may be exerted by the
same mechanism. However, the precise mechanism of its action should be
clarified.
As shown in this study,
1,25(OH)2D3 increased
expression of the OPN gene (Figure 4b
1,25(OH)2D3 is well known
to be a potent stimulator of osteoblastic differentiation and to
increase gene expression of differentiation markers such as OPN and
osteocalcin.31 Vascular calcification has several
features similar to those of bone mineralization, including expression
of BMP-2, ALP, OPN, osteonectin, and osteocalcin and hydroxyapatite
crystal formation in calcified atherosclerotic
lesions.5 6 7 8 9 10 32 33 Therefore, it is hypothesized
that in the development of vascular calcification associated with
atherosclerosis, VSMCs may differentiate into
osteoblastic cells via several factors, including BMPs, and that this
process may be promoted by the action of
1,25(OH)2D3. These
hypotheses should be proved through further investigations.
An association between osteoporosis and vascular calcification with
aging has been well documented in several
studies.11 12 13 14 Vitamin D deficiency is common in
the elderly and may contribute to bone loss by causing increased levels
of PTH.34 35 Therefore, it is presumed that
vitamin D deficiency may be involved in the pathogenesis of vascular
calcification. Recently, it was reported that active serum vitamin D
levels are inversely correlated with coronary
calcification.20 This finding seems to suggest
the protective roles of vitamin D in vascular calcification and to
support the above-mentioned hypothesis. However, the vast majority of
its values presented in the study were within normal
range,20 and serum levels of 25-hydroxyvitamin D
(25OHD), a serum marker for nutritional status of vitamin D, were not
documented. Therefore, it is not clear whether vitamin D deficiency may
contribute to such inverse correlation. Further studies are necessary
to confirm the hypothesis.
Because vitamin D and calcium supplementation are widely used for the
treatment of osteoporosis, especially in the
elderly,36 it is important to determine whether
long-term supplementation of vitamin D for osteoporosis exacerbates
vascular calcification. It is suggested from the present study that
pharmacological doses of
1,25(OH)2D3 may stimulate
vascular calcification through a direct action on VSMCs. However, high
doses of oral vitamin D, which induces vascular calcification in
experimental animals, do not always increase serum levels of
1,25(OH)2D, but 25OHD is
increased,15 37 38 because the serum level
of 1,25(OH)2D is strictly regulated within the
narrow range by PTH, regardless of the nutritional status of vitamin D.
The mechanism by which increased levels of serum 25OHD induce vascular
calcification remains to be clarified. Local production of
1,25(OH)2D by 1
Received January 21, 1998;
revision received May 26, 1998;
accepted June 6, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
1,25-Dihydroxyvitamin D3 Increases In Vitro Vascular Calcification by Modulating Secretion of Endogenous Parathyroid Hormone–Related Peptide
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—A significant
association between vascular calcification and osteoporosis has been
noted, suggesting that calcium homeostasis is important in vascular
calcification as well as in osteoporosis. Moreover, results of our
previous studies suggest that calcium-regulating hormones such as
parathyroid hormone–related peptide (PTHrP) may modulate vascular
calcification. Therefore, we hypothesized that 1
,25-dihydroxyvitamin
D3 [1,25(OH)2D3] may have a
direct impact on the calcium-regulating system of vascular smooth
muscle cells, resulting in deposition of calcium in vascular
wall.
Key Words: calcification • vitamin D • muscle, smooth • peptides • osteoporosis
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Calcification is almost invariably associated with
atherosclerotic plaque formation.1 2 3 Recently,
it was hypothesized that plaque calcification is an active, regulated
process similar to osteogenesis.4 Bone
morphogenetic proteins (BMPs), including BMP-2, and bone matrix
proteins, such as osteopontin (OPN), osteonectin, and osteocalcin, have
been demonstrated in atherosclerotic plaques, especially calcified
lesions, through immunohistochemistry and in situ
hybridization.5 6 7 8 9 However, details of the
mechanism by which vascular calcification is induced remain
unclear. Using an in vitro model of vascular calcification, we
demonstrated that the expression of alkaline phosphatase (ALP) is
functionally important in the calcification of bovine vascular smooth
muscle cells (BVSMCs) and that OPN mRNA is expressed exclusively in
calcified BVSMCs.10 Therefore, it is likely that
vascular smooth muscle cells (VSMCs) acquire calcifying capacity under
certain conditions. ,25-Dihydroxyvitamin D3
[1,25(OH)2D3], an active
metabolite of vitamin D, can exert a direct effect on VSMCs,
which express vitamin D receptors.17
1,25(OH)2D3 stimulates
acute calcium influx into VSMCs and inhibits proliferation of
VSMCs.18 19 Moreover, serum levels of
1,25(OH)2D3 are inversely
correlated with coronary calcification.20
Excess vitamin D induces vascular calcification in both humans and
experimental animals21–23; therefore, it is
important to clarify whether the therapeutic use of vitamin D for
osteoporosis promotes atherosclerosis and vascular
calcification. However, the detailed mechanisms of the actions of
vitamin D on VSMCs remain unclear.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Reagents
Media, FBS, and sodium pyruvate were purchased from GIBCO.
ß-Glycerophosphate (ß-GP) was obtained from Sigma Chemical Co.
1,25(OH)2D3 was obtained
from Solvay Duphar BV. Human PTHrP (fragment 1-34) was obtained from
Peptide Institute. Human PTHrP cDNA probe containing a 451–base pair
fragment (corresponding to -5 to 446 in its full-length
cDNA16) was a kind gift of Dr M. Hino (Department
of Clinical Hematology, Osaka City University Medical School,
Osaka, Japan). Unless otherwise mentioned, all other reagents were
obtained from Wako Pure Chemical Industries, Ltd.
BVSMCs were obtained by explantation as previously
described.10 Cells that had migrated from the
explants were collected and maintained in DMEM (high glucose, 4.5 g/L
glucose) containing 15% FBS and 10 mmol/L sodium pyruvate
supplemented with 100 U/mL penicillin and 100 µg/mL streptomycin
(growing medium) at 37°C in a humidified atmosphere containing 5%
CO2. Cells up to passage 8 were used for the
experiments. BVSMC calcification was induced as previously
described.10 Briefly, BVSMCs were cultured in the
growing medium. After confluence, the cells were inoculated in DMEM
(high glucose, 4.5 g/L) containing 15% FBS and 10 mmol/L sodium
pyruvate in the presence of 10 mmol/L ß-GP supplemented with 100
U/mL penicillin and 100 µg/mL streptomycin (calcification medium) for
72 hours.
Cells were decalcified with 0.6N HCl for 24 hours. The calcium
content of HCl supernatant was determined
colorimetrically by the o-cresolphthalein
complexone method (calcium C-test Wako; Wako Pure Chemical
Industries).16 After decalcification, cells were
washed 3 times with PBS and solubilized with 0.1N NaOH/0.1% SDS.
Protein content was measured with a BCA protein assay kit (Pierce).
Calcium content of the cell layer was normalized by protein content.
We assessed secretion of PTHrP by BVSMCs by measuring the PTHrP
content of the culture supernatant with an immunoradiometric assay kit
(PTHrP IRMA kit; Mitsubishi Kagaku).16 The
supernatant was collected in the presence of 10 µg/mL aprotinin and
1 mmol/L EDTA after the fresh medium containing 15% FBS was
incubated for 72 hours with BVSMCs on a six-well plate. The content of
PTHrP in the medium containing 15% FBS incubated for 72 hours without
the cells was estimated as the background. The net quantity of PTHrP
secreted from BVSMCs was estimated by subtracting the PTHrP content of
the background from that in the cell culture supernatant. Finally, the
data were normalized by the protein content of the cell layer.
After the cells were washed twice with PBS, the cellular
proteins were solubilized with 1% Triton X-100 in 0.9% NaCl and
centrifuged, and the supernatants were assayed for ALP activity
as described previously.10 One unit was defined
as the activity producing 1 nmol of p-nitrophenol for 30
minutes. Protein concentrations were determined with a BCA protein
assay kit (Pierce).
Total RNA was isolated from BVSMCs by extraction with acid
guanidinium thiocyanate–phenol–chloroform. Twenty micrograms of total
RNA was electrophoresed onto 1% agarose gels containing formaldehyde
and transferred to a nylon filter (Hybond N; Amersham International).
Blots were prehybridized at 37°C for 24 hours in a buffer containing
50% formamide, 3x SSC (1x SSC, 0.15 mol/L NaCl, and 15 mmol/L
sodium citrate, pH 7.4), 50 mmol/L Tris-HCl, pH 7.5, 0.1% SDS, 20
µg/mL denatured salmon sperm DNA, and 1x Denhardt's solution and
then hybridized at 37°C for 48 hours with cDNA probes for human PTHrP
or bovine OPN that were labeled with
[-32P]dCTP (3000 Ci/mL; New England Nuclear
Research Products) by use of a random priming method (Megaprime
cDNA labeling system, Amersham). Blots were washed and autoradiographed
with x-ray film at -70°C. The amounts of RNA were quantified by
densitometric scanning and normalized by comparison with GAPDH.
In certain experiments, data were analyzed for
statistical significance by ANOVA with posthoc analysis
(Fisher's protected least significant difference [PLSD]). These
analyses were performed with the assistance of a computer
program (StatView Version 4.11; Abacus Concepts).
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
We first examined the effect of
1,25(OH)2D3 on BVSMC
calcification. 1,25(OH)2D3
promoted this calcification in a dose-dependent manner, and the calcium
content of the cell layer increased to 470% of the calcified control
at 10–7 mol/L (Figure 1
). Because ALP plays an important role
in BVSMC calcification, as previously reported,10
we next examined the effect of
1,25(OH)2D3 on ALP activity
in BVSMCs. As we previously reported, ALP activities were increased in
each group in the presence of ß-GP (calcified condition) compared
with its absence (uncalcified condition)10
(Figure 2).
1,25(OH)2D3 dose
dependently increased ALP activities in both uncalcified and calcified
BVSMCs, and at 10–7 mol/L, ALP activities
increased to 168% and 167% of the control, respectively (Figure 2).
These data suggest that the stimulatory effect of
1,25(OH)2D3 on
calcification may be due to increased ALP activity.
View larger version (19K):
[in a new window]
Figure 1. Effect of 1,25(OH)2D3 on
BVSMC calcification. Cells were cultured in calcification medium for 72
hours in the presence of the indicated concentrations of
1,25(OH)2D3. ß-GP (+) and (-) indicate
presence and absence of ß-GP, respectively. Calcium contents were
measured by the o-cresolphthalein complexone method, and
normalized by cellular protein content and are presented as
mean±SEM. Differences compared with calcified control were
statistically significant (*P<0.05, Fisher's
PLSD).
View larger version (26K):
[in a new window]
Figure 2. Effect of 1,25(OH)2D3 on
ALP activity. Cells were cultured in calcification medium for 72 hours
in the presence of the indicated concentrations of
1,25(OH)2D3. ß-GP (+) and (-) indicate
presence and absence of ß-GP, respectively. ALP activities were
measured and normalized by cellular protein content and are
presented as mean±SEM. Differences compared with each control
(CTL) were statistically significant (*P<0.05,
Fisher's PLSD). ), as
previously reported.16
1,25(OH)2D3 dose
dependently decreased PTHrP secretion by BVSMCs under both uncalcified
and calcified conditions, and at 10–7 mol/L,
PTHrP levels decreased to 34% and 43% of each control, respectively
(Figure 3). Moreover,
1,25(OH)2D3 inhibited the
expression of PTHrP mRNA in BVSMCs ranging from
10–10 to 10–7 mol/L, and
at 10–7 mol/L, the mRNA level decreased to
71.4% of control (Figure 4a). These data
suggest that 1,25(OH)2D3
directly modulates PTHrP expression in BVSMCs. Therefore, we
hypothesized that
1,25(OH)2D3 increases in
vitro calcification by inhibiting PTHrP secretion by BVSMCs. To prove
this hypothesis, we performed an add-back experiment to examine whether
exogenous PTHrP antagonizes the stimulatory effect of
1,25(OH)2D3 on BVSMC
calcification. Human PTHrP (fragment 1-34) dose dependently antagonized
the effect of 1,25(OH)2D3
on this calcification and almost completely blocked its effect at
10–7 mol/L (Figure 5), suggesting that
1,25(OH)2D3 exerts its
stimulatory effect on BVSMC calcification through inhibition of
endogenous PTHrP secretion.
View larger version (21K):
[in a new window]
Figure 3. Effect of 1,25(OH)2D3 on
PTHrP secretion by BVSMCs. Cells were cultured in calcification medium
for 72 hours in the presence of the indicated concentrations of
1,25(OH)2D3. ß-GP (+) and (-) indicate
presence and absence of ß-GP, respectively. After a 72-hour culture
in the presence of the indicated concentrations of
1,25(OH)2D3, PTHrP contents were measured by
immunoradiometric assay, corrected, and normalized. Data are
presented as mean±SEM. Differences compared with each control
(CTL) were statistically significant (*P<0.05,
Fisher's PLSD).
View larger version (45K):
[in a new window]
Figure 4. Effects of 1,25(OH)2D3 on
gene expressions of PTHrP (a) and OPN (b). Cells were cultured in
calcification medium for 24 hours in the presence of the indicated
concentrations of 1,25(OH)2D3. After a 24-hour
culture in the presence of the indicated concentrations of
1,25(OH)2D3, cells were harvested for isolation
of total RNA. Twenty micrograms of total RNA from BVSMCs was
electrophoresed, blotted, and probed with cDNA of human PTHrP. a,
Autoradiograph of Northern analysis of PTHrP. b, Autoradiograph
of Northern analysis of OPN. CTL indicates control.
View larger version (21K):
[in a new window]
Figure 5. Effect of human PTHrP (fragment 1-34) on
1,25(OH)2D3-stimulated BVSMC calcification.
Cells were cultured in calcification medium for 72 hours in the
presence of the indicated reagent or reagents. Calcium contents were
measured by the o-cresolphthalein complexone method and
normalized by cellular protein content and are presented as
mean±SEM. Differences compared with the
1,25(OH)2D3-treated control were statistically
significant (*P<0.05, Fisher's PLSD). ß-GP
indicates 10 mmol/L ß-GP; 1,25(OH)2D3,
10–7 mol/L 1,25(OH)2D3; and (+)
and (-), presence and absence of the indicated reagent,
respectively. 
). Therefore, upregulation of OPN gene by
1,25(OH)2D3 may contribute
to its stimulatory action on BVSMC calcification.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In this study, we demonstrated a possible mechanism by which
1,25(OH)2D3 stimulates
vascular calcification through a direct action on VSMCs. Although it
has been well documented that a high dose of vitamin D induces vascular
calcification in humans and experimental
animals,21 22 23 the mechanism of its stimulatory
action in vivo on vascular calcification remains to be clarified. We
recently demonstrated that PTHrP secreted by VSMCs acts as an
endogenous inhibitor of vascular
calcification.16 Therefore, we hypothesized that
PTHrP is one of the molecular targets of the action of
1,25(OH)2D3 on VSMCs. As
shown in the present study,
1,25(OH)2D3 directly
modulates the expression of PTHrP in BVSMCs at both protein and gene
levels, contributing to its action on vascular calcification (Figures 3, 4a, and 5). Therefore, it is likely that VSMCs are equipped with an
autocrine/paracrine system that regulates calcium
metabolism and that
1,25(OH)2D3 affects this
local system to exert its stimulatory action on vascular
calcification. ) as well as in vitro
calcification by BVSMCs. We have previously demonstrated that
expression of the OPN gene is dramatically increased in calcified
BVSMCs.10 In our preliminary experiments,
recombinant OPN dose dependently increased this calcification
(Jono et al, unpublished observation, 1997). Therefore,
upregulation of the OPN gene by
1,25(OH)2D3 may contribute
to the promotion of BVSMC calcification. The mechanism of upregulation
of this gene by 1,25(OH)2D3
has been investigated extensively in osteoblastic
cells.27 28 29 30
1,25(OH)2D3 increases
transcriptional activity of the gene, which has a vitamin D response
element composed of 2 direct repeats within its promoter
region.30 It is likely that
1,25(OH)2D3 exerts its
effect on OPN expression in BVSMCs by the same mechanism. -hydroxylase expressed in
macrophages accumulated in atherosclerotic lesions may be
involved in this process.39 Therefore, it is
important to monitor serum levels of 25OHD during vitamin D
supplementation. If serum levels of 25OHD are increased beyond the
normal range, vascular calcification may develop even within normal
levels of 1,25(OH)2D.
Acknowledgments
This work was supported in part by a grant-in-aid for Scientific
Research (09770793) from the Ministry of Education, Science, and
Culture of Japan. We thank Dr M. Hino for kindly providing the human
PTHrP cDNA probe.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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D. Somjen, Y. Weisman, F. Kohen, B. Gayer, R. Limor, O. Sharon, N. Jaccard, E. Knoll, and N. Stern 25-Hydroxyvitamin D3-1{alpha}-Hydroxylase Is Expressed in Human Vascular Smooth Muscle Cells and Is Upregulated by Parathyroid Hormone and Estrogenic Compounds Circulation, April 5, 2005; 111(13): 1666 - 1671. [Abstract] [Full Text] [PDF]
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M. Rodriguez, E. Nemeth, and D. Martin The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism Am J Physiol Renal Physiol, February 1, 2005; 288(2): F253 - F264. [Abstract] [Full Text] [PDF]
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P.E. Norman and J.T. Powell Vitamin D, Shedding Light on the Development of Disease in Peripheral Arteries Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 39 - 46. [Abstract] [Full Text] [PDF]
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C. M. Giachelli Vascular Calcification Mechanisms J. Am. Soc. Nephrol., December 1, 2004; 15(12): 2959 - 2964. [Abstract] [Full Text] [PDF]
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S. M. Moe and N. X. Chen Pathophysiology of Vascular Calcification in Chronic Kidney Disease Circ. Res., September 17, 2004; 95(6): 560 - 567. [Abstract] [Full Text] [PDF]
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 R. Vattikuti and D. A. Towler Osteogenic regulation of vascular calcification: an early perspective Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E686 - E696. [Abstract] [Full Text] [PDF]
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T. Shoji, K. Shinohara, E. Kimoto, M. Emoto, H. Tahara, H. Koyama, M. Inaba, S. Fukumoto, E. Ishimura, T. Miki, et al. Lower risk for cardiovascular mortality in oral 1{alpha}-hydroxy vitamin D3 users in a haemodialysis population Nephrol. Dial. Transplant., January 1, 2004; 19(1): 179 - 184. [Abstract] [Full Text] [PDF]
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 J.-S. Shao, S.-L. Cheng, N. Charlton-Kachigian, A. P. Loewy, and D. A. Towler Teriparatide (Human Parathyroid Hormone (1-34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice J. Biol. Chem., December 12, 2003; 278(50): 50195 - 50202. [Abstract] [Full Text] [PDF]
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