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Wnt Osteoblast Pathway and Ostoprotegerin
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an interaction between bone metabolism and vascular health, placing current
understanding of vascular pathophysiology on a bone-vascular axis [3].
BONE TURNOVER, VASCULAR CALCIFICATIONS AND
ARTERIAL STIFFNESS
Arterial stiffness increases with advancing age even in individuals
at low risk for cardiovascular disease and is a predictor of hypertension,
decline in cognitive function and morbidity and mortality, independent
of well-established traditional cardiovascular risk factors [9, 10]. Aging
is also associated with bone demineralization, a process that is accelerated
in women compared to men. Several lines of evidence suggest
that age-associated bone demineralization and arterial calcification
share common pathogenetic mechanisms [11]. Moreover, accumulating
epidemiologic, as well as experimental evidence, supports an inverse
correlation between bone turnover and premature arteriosclerosis, associated
with vascular calcifications, both in general population and specific patient
groups, including elderly individuals, post-menopausal women and CKD
patients [12, 13]. In accordance with the above, several studies in different
patient populations reported a correlation between osteoporosis and fractures
with vascular calcifications. In a Spanish cohort of 624 men and women older
than 50 years a positive association was shown between aortic calcifications at
baseline and osteoporotic fractures, as well as between aortic calcifications’
progression and bone mineral density (BMD) decline rate at lumbar spine,
during a 4-year follow-up period [14]. A cross-sectional study (the Baltimore
Longitudinal Study of Aging) in 633 men and women reported an inverse
correlation between arterial stiffness, assessed by carotid-femoral pulse wave
velocity (PWV) and cortical bone area, evaluated at the level of the mid-tibia
with computed tomography imaging) only in women. This association was
independent of age and other covariates, including renal function, physical
activity, menopause, obesity, drugs, alcohol intake, serum calcium, total
estradiol concentration and mean arterial pressure (MAP) [15]. Finally, in 193
hemodialysis (HD) patients, calcifications in the medium calibre arteries were
found to be associated with a higher rate of prevalent vertebral fractures during
the 2-year follow-up period. Moreover, mortality was shown to be increased in
women with severe vascular calcifications and vertebral fractures [16].
Recent evidence indicates that bone proteins produced by osteocytes and
osteoblasts and involved in bone anabolic and catabolic pathways exert also
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effects on arterial calcification and stiffening. Among them, the inhibitors of
the canonical Wnt/β-catenin signaling pathway of the osteoblasts, such as
sclerostin and Dickkopf-related protein-1 (DKK-1), and the pathway of
the osteoclasts inhibitor of the receptor activator of nuclear factor κB
(RANK)/RANK ligand (RANKL)/ osteoprotegerin (OPG), have been mostly
studied to date.
WNT/β-CATENIN PATHWAY AND BONE TURNOVER
For more than a decade, the role of Wnt/β-catenin pathway in bone
metabolism has been the focus of basic and clinical research. Activation of
Wnt/β-catenin signaling increases bone formation and decreases bone
resorption and is tightly regulated by several inhibitors, among which
sclerostin and DKK1 have been more thoroughly studied [13, 17, 18].
Sclerostin and DKK-1 are small glycoproteins (MW 28 and 26 respectively),
expressed in osteocytes. Both proteins bind to low-density lipoprotein
receptor-related protein (LRP) 5/6 of the osteoblasts and inhibit Wnt/β-catenin
signaling pathway, blocking osteoblast differentiation and function and
thereby inhibiting bone formation and mineralization [18]. In addition,
sclerostin regulates synthesis of hormones that affect bone formation and
mineralization, including fibroblast growth factor-23 (FGF-23) and calcitriol,
as well as urinary calcium excretion [19]. Multiple factors appear to affect
sclerostin and DKK1 expression in osteocytes; thus, calcitonin, bone
morphogenetic proteins, diabetes and mediators of inflammation increase,
whereas parathyroid hormone, transforming growth factor-β (TGF-β)
estrogens and skeletal mechanical stress decrease their expression [18, 20-22].
Finally, apart from osteocytes, Wnt/β-catenin pathway inhibitors were found
to be expressed in other tissues; sclerostin is expressed vascular smooth
muscle cells, chondrocytes, aortic valves and kidney and DKK-1 in skin,
kidney, platelets, endothelium, placenta and prostate [23, 24].
WNT/β-CATENIN PATHWAY, VASCULAR CALCIFICATIONS
AND ARTERIAL STIFFNESS
Recently mounting evidence mainly from experimental studies, suggests
that Wnt signaling is also implicated in the cross talk between bone and the
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vasculature and the pathogenesis of vascular calcifications and stiffening.
However, studies investigating the probable associations between circulating
levels of these inhibitors with vascular calcifications, arterial stiffness and
adverse clinical outcomes in different patient groups are limited and some
results are inconsistent. Apart from the differences in patient populations,
differences in the methods used to determine circulating levels of these factors
and in the assessment of vascular calcifications and arterial stiffening may be,
at least partially, responsible for the discrepant results.
Sclerostin, Vascular Calcifications and Arterial Stiffness
Several studies have demonstrated that circulating sclerostin levels are
increasing with age and renal function decline and are higher in men than
women [11]. In a study in 90 CKD stage 3-5 patients, sclerostin levels, were
reported to be two- to fourfold higher compared with subjects with normal
renal function and were highest in those with end-stage renal disease (ESRD).
An inverse relationship was found between sclerostin and estimated
glomerular filtration rate (eGFR) and a positive correlation with age and serum
phosphate. In multiple regression analyses, eGFR, sex, and serum phosphate
were the only variables associated with serum sclerostin, whereas age lost its
relationship with sclerostin level [25]. In addition, sclerostin levels were found
to decrease rapidly after a successful renal transplantation in parallel to renal
function improvement [26]. Interestingly, a recent study suggested that
increased sclerostin levels in CKD are not due to decreased renal elimination.
In the above study in 125 CKD stage 1-5 patients, urinary sclerostin excretion
increased with declining eGFR. Fractional sclerostin excretion also increased
with falling eGFR and was correlated with fractional excretion of α1-
microglobulin. Of note, sclerostin was detected in proximal tubular cells,
showing a diffuse cytoplasmic staining pattern [27]. Moreover, a study in
CKD patients showed that sclerostin mRNA levels in bone biopsy specimens
were not increased, in spite of high circulating levels suggesting that elevated
sclerostin in this population could be attributable to enhanced extraskeletal
(vascular) production [28].
Several studies investigated the correlations between sclerostin levels and
vascular calcifications and arterial stiffness. In 146 post-menopausal women a
significant positive correlation was observed between sclerostin levels and
abdominal aortic calcifications detected and quantified, using Vertebral
Fracture Assessment imaging as well as arterial stiffness, assessed by aortic
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PWV [29]. In addition, in rheumatoid arthritis patients, sclerostin levels were
found to be significantly and independently associated with abdominal aortic
calcifications evaluated by computed tomography [30]. However, in a study
in 154 CKD patients sclerostin levels had a positive association with the
presence of aortic calcifications, but, after adjustment for other significant
factors including age, gender and eGFR, this association became inverse [31].
Interestingly, a study in 67 chronic hemodialysis (HD) patients, showed a
strong association between sclerostin and calcifying aortic heart valve disease
assessed by multi-slice computed tomography. Moreover, ex vivo analysis of
uremic calcified aortic valves revealed a strong sclerostin expression very
close to calcified regions and no sclerostin staining in non-calcified valves.
Correspondingly, a highly significant up-regulation of sclerostin mRNA in
calcified valves compared to non-calcified control valves was observed [32].
The above results are consistent with an experimental study, which
demonstrated that sclerostin was up-regulated during vascular smooth muscle
cell calcification in vitro. Moreover sclerostin, expressed by more mature
osteocytes was also observed in the calcified media of mouse aortic tissue
[33]. Another cross-sectional study in 122 prevalent HD patients, reported
augmented serum sclerostin levels in patients with plaques in common carotid
artery identified with ultrasound imaging, when compared to free of plaques
patients [34]. In accordance with the aforementioned results, a recent clinical
trial conducted in 89 ESRD patients, showed that high serum sclerostin levels
are associated with the extent of vascular calcification, as evaluated both by
coronary artery computed tomography and scoring of epigastric artery
calcification. Of note vascular sclerostin mRNA and protein expressions were
low or absent and did not differ between calcified and non-calcified vessels,
suggesting that the vasculature is not a major contributor to circulating levels
[35]. Finally, a study in 77 pre-dialysis CKD patients reported no association
between sclerostin levels and arterial stiffness, determined by contour analysis
of digital volume pulse [36]. In contrast, a study in 68 renal transplant
recipients showed that serum sclerostin levels were associated with peripheral
arterial stiffness, measured by brachial-ankle PWV [37]. Overall, the above
findings indicate that sclerostin is produced locally during extraosseous
calcification and released into the systemic circulation, resulting in increased
serum levels. Moreover, it appears tempting to speculate that the detection of
sclerostin upregulation in calcified vascular tissues represent a feedback
mechanism delaying mineralization process. In support of this hypothesis,
sclerostin was found to potently suppress alkaline phosphatase activity and
inhibit hydrolysis and inactivation of inorganic pyrophosphate which prevents
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hydroxyapatite crystal growth, acting as local and circulating inhibitor of
vascular calcification [38]. However, additional experimental and clinical
studies are required to clarify whether or not sclerostin protects against
vascular calcification.
Studies examining the probable correlation of serum sclerostin with
clinical outcomes and mortality are scarce and inconclusive. A study in 173
CKD stage 3-5 patients reported a positive association between sclerostin
levels and fatal and non-fatal CV events during follow-up [39]. Also, in 91
hemodialysis patients followed during a ten-year period elevated sclerostin
levels were found to be independently associated with higher mortality [40]. In
contrast, another study in 100 prevalent hemodialysis (HD) patients followed
for median 637 days, found that higher circulating sclerostin levels were
associated with decreased mortality; however, when bone specific alkaline
phosphatase entered the Cox regression analysis, it replaced sclerostin [41]. In
line with the above, a very recent prospective cohort study in 673 incident
dialysis patients, demonstrated that patients in the highest sclerostin tertile
had a significantly lower risk of short-term (18 months) cardiovascular death
and all-cause mortality compared with patients of the lowest tertile, after
adjustment for various clinical and biochemical parameters. The association of
sclerostin levels with outcome was less pronounced for long-term (4 years)
cardiovascular mortality and absent for non-cardiovascular mortality [42].
Finally, another study in 164 HD patients failed to demonstrate any association
between sclerostin levels and mortality during the 2-year follow-up period
[43]. Nevertheless, the potential value of serum sclerostin concentrations as a
predictor of mortality in different patient populations needs to be further
investigated.
DKK-1, Vascular Calcifications and Arterial Stiffness
In contrast to sclerostin, aging, gender and renal function appear
to minimally affect DKK-1 levels [29, 36]. Moreover, studies investigating
the correlations between DKK-1 levels, vascular calcifications and arterial
stiffness in different patient populations are limited. In a study in 1139
male volunteers from the general population, severity of abdominal aortic
calcifications, assessed on the lateral spine scans, increased with decreasing
DKK-1 levels, independently of age and other potential confounders [44]. In
addition, in the aforementioned study in 146 post-menopausal women, there
was a significant negative correlation between DKK-1 and abdominal aortic
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calcification, which remained significant following correction for age, blood
pressure and cholesterol. However, no association was observed between
DKK-1 and arterial stiffness [29]. Finally, a study in 450 African-Americans
with type 2 diabetes showed that plasma DKK-1 levels were inversely
associated with coronary artery and aortoiliac atherosclerotic calcified plaques
[45]. In contrast, a study in 270 consecutive patients showed that DKK-1 is an
independent risk factor for the presence of coronary atherosclerotic plaque
identified by contrast-enhanced coronary multiple detector computed
tomography. In the above study, patients with the highest quartile of DKK-1
concentrations demonstrated coronary atherosclerotic plaques even when they
had low Agatston calcium score [46]. In addition, a study in 218 consecutive
patients who were undergoing cardiac catheterization because of symptomatic
calcified aortic stenosis showed that coronary atherosclerosis was related to
significantly lower DKK-1 levels. However, a positive association was found
between DKK-1 and calcium load in aortic valve in patients with symptomatic
calcified aortic stenosis and angiographically normal coronary arteries [47].
Moreover, a study in patients with symptomatic aortic stenosis revealed that
DKK-1 serum levels were markedly elevated and were present in calcified
aortic valves but correlated poorly with systemic levels or degree of aortic
stenosis. Interestingly, DKK-1 predicted long-term mortality (median 4.6
years) in these patients after adjusting for conventional predictors including
NT-proBNPn [48].
In accordance with the reported negative association of DKK-1 levels with
extraosseous calcifications, a previously mentioned study in 77 CKD stage 3
patients, showed that DKK-1 levels were inversely correlated with arterial
stiffness index determined by contour analysis of digital volume pulse [36].
However, a study in renal transplant recipients failed to demonstrate any
correlation of serum DKK-1 levels with peripheral arterial stiffness measured
by brachial-ankle pulse wave velocity [37]. There are no published data on the
relationship between circulating DKK-1 levels and mortality apart from the
aforementioned study in patients with symptomatic aortic stenosis [48].
OSTEOPROTEGERIN/RANK/RANKL PATHWAY AND
BONE METABOLISM
Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor kB
(RANK) and Receptor Activator of Nuclear Factor kB ligand (RANKL)
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are members of the tumor necrosis factor (TNF) superfamily which
were originally studied as factors involved in bone turnover activation
and immune system physiology. RANK/RANKL/OPG signaling pathway
regulates osteoclast differentiation and activation. OPG is a soluble
glycoprotein widely expressed in most human tissues including bone
(osteoblasts, mesenchymal stem cells), immune cells (T and B cells) and
vessels (endothelial and VSMCs). RANKL is a transmembrane protein
consisted of 316 aminoacids, which is expressed on osteoblasts, stromal and T
cells in areas of bone remodeling. RANKL binds to its receptor RANK, a 616
amino acid type I transmembrane protein which is expressed on the surface of
myeloid cell lineages like osteoclasts, monocytic and dendritic cells and
activates multiple intracellular signals, thereby regulating the differentiation,
function and survival of these cells. OPG acts as a decoy receptor and binds to
RANKL, thereby not allowing the activation of RANK and inhibits its
regulatory effects on inflammation, skeletal and vascular systems [49, 50].
OPG also has anti-apoptotic actions, as it binds and deactivates the TNF
related apoptosis-inducing ligand (TRAIL), which is expressed by many cell
types, including VSMCs, and can also lead to ectopic mineralization [51].
OPG’s expression is increased by vitamin D, TNF-α, IL-1α, IL-6, IL-11 and
IL-17, bone morphogenic protein-2 (BMP-2), TGF-β and estrogens, whereas it
is reduced by PTH, corticosteroids and prostaglandin E2 [49, 50].
OSTEOPROTEGERIN, VASCULAR CALCIFICATIONS
AND ARTERIAL STIFFNESS
Mounting evidence suggests that OPG constitutes a link between bone
metabolism and vascular pathophysiology by controlling simultaneously bone
remodeling and vascular calcification mechanisms [52-54]. OPG inhibits
ostoeoclastogenesis and promotes bone mineralization. In addition, it exerts
actions on both endothelial cells and VSMCs and consequently participates in
multiple processes that regulate vascular calcification. The implication of OPG
in vascular pathophysiology is supported by its expression in the normal
cardiovascular system (heart, arteries and veins). OPG is constitutively
expressed on endothelial cells promoting their survival and VSMCs preventing
their osteogenetic differentiation [49].
Moreover, studies suggested that OPG expression might reflect a
protective mechanism against the vascular calcifications. Thus, over-
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expression of OPG leads to osteopetrosis, while its gene’s depletion increases
bone metabolism and leads to osteoporosis and medial calcifications in the
aorta and the renal arteries [55, 56]. In addition, OPG administration in
laboratory animals was reported to potently reduce both bone resorption and
medial arterial calcifications induced by administration of toxic doses of
vitamin D or warfarin [57].
In the general population, studies have demonstrated that high levels of
OPG are correlated with cardiovascular risk [58, 59]. In addition, the
aforementioned study in symptomatic calcified aortic stenosis showed that the
presence of coronary atherosclerosis was related to significantly higher OPG
levels [47]. In hypertensive patients serum OPG levels were found to
be independent predictor of PWV values, following multivariable forward
stepwise linear regression analysis of the significant variables, including age,
systolic blood pressure, pulse pressure, glomerular filtration rate [60]. Finally,
in a study in 1939 adults with type 1 diabetes, OPG concentrations at
baseline predicted an incident cardiovascular event and peripheral vascular
disease/amputation events during a mean follow-up of more than 10 years
[61]. In CKD patients, it has been shown that OPG levels significantly
increase along with the decline in GFR and are reduced after a successful renal
transplantation [62]. However, studies examining the association of OPG
levels with the presence and extent of cardiovascular calcifications and arterial
stiffness are relatively limited and their results were sometimes inconsistent.
Thus, in non-dialyzed CKD patients a cut-off value of OPG level was found to
predict the presence of coronary artery calcifications (CAC) assessed by chest
multi detector computed tomography [63]. Another study in ESRD patients, on
conservative treatment or on dialysis, showed that renal function rather than
OPG levels was associated with the progression of aortic and coronary
calcifications [64]. In addition, in HD patients, one study showed correlation
of elevated OPG only with moderate CAC, while another reported that
OPG is a predictor of high CAC score [65, 66]. Also, in HD patients, an
association between OPG and aortic calcification index, assessed by computed
tomography scans, was reported, independently of traditional and uremia-
related risk factors [67]. In addition, high OPG levels have been also found to
correlate with faster progression of aortic calcifications during a 5-year follow-
up [68]. In transplanted patients, CAC score at baseline, but not 1 year after
renal transplantation, was found to be independently associated with baseline
OPG, whereas post-transplant coronary artery calcification progression was
predicted by baseline CAC score [69]. Similarly, in, another study, baseline
OPG levels were also significantly and independently associated with the
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progression of aortic calcification index assessed by lateral lumbar x-ray
during a two-year follow-up period [70].
In a study in 351 CKD patients increasing tertiles of serum
osteoprotogerin were associated with higher aortic PWV after adjustment for
demographics, traditional vascular risk factors, and a variety of non-traditional
risk factors, including eGFR and albuminuria [71]. In addition, the majority of
studies in adults and children on hemodialysis treatment confirmed the
significant and independent association between OPG levels and carotid-
femoral PWV [7, 72-76]. Moreover, one of the above studies demonstrated
that higher OPG levels may be independent predictors of new cardiovascular
events [76] and two others showed a significant correlation between
osteoprotegerin levels and cardiovascular, as well as all-cause mortality during
follow-up, independently of several traditional and uremia-related risk factors
[74, 75]. Some studies in patients with various CKD stages, as well as in renal
transplant recipients, confirmed the independent predictive value of OPG
levels for all-cause and cardiovascular mortality during the follow-up period
[77-79].
Although the exact role of OPG in the vascular calcification process
remains to be fully elucidated, since OPG knockout mice develop arterial
calcifications, it appears reasonable to assume that it plays some regulatory
and/or inhibitory role against ectopic calcifications and thus its increased
levels could be interpreted as an attempt to compensate for the ongoing
calcification process. [74, 75, 77, 78]. The above speculation contradicts the
reported association of high OPG levels with cardiovascular mortality [59, 74,
75] and moreover, increase of OPG levels could be due to its production by
calcified vascular cells in conditions of diffuse calcification [80]. Thus, further
experimental and clinical studies are required to clarify whether the elevated
OPG levels induce arterial wall sclerosis or represent a compensatory
mechanism to prevent further arterial damage or are just a marker of initiation
of vascular calcification process [81]. Interestingly, a recent study suggested
that the two opposite bone turnover inhibitors, sclerostin and OPG, under
certain conditions, could have a synergistic effect on vascular calcifications. In
this study in 241 CKD patients, the presence of CAC, assessed by chest multi
detector computed tomography was associated with high OPG and sclerostin
concentrations. Moreover, logistic regression analyses clearly showed that the
risk to present CAC was significantly increased when both OPG and sclerostin
levels were high after adjusting for age, gender, diabetes, body mass index and
smoking habits. Notably, this synergistic impact was observed in case of low
or normal PTH levels [82]. Sclerostin and OPG both increase in parallel with
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renal function decline, leading potentially to low bone turnover. However,
PTH which is also increased with advancing CKD, increases bone turnover
and counterbalances the adverse impact of these two bone inhibitors in the
vasculature [82, 83].
FUTURE PERSPECTIVES AND CONCLUSION
Experimental and clinical studies have identified both anabolic and
catabolic bone turnover pathways as key players in the development and
progression of arterial calcification and stiffening. Among the inhibitors of
bone turnover and mineralization, sclerostin, DKK-1 and OPG are the mostly
studied, but their exact role in vascular disease and their probable association
with adverse clinical outcomes in different patient populations remain to be
elucidated. However, experimental studies suggest that antibodies against
sclerostin or DKK-1 in animal models improve bone formation rate and
prevent CKD-stimulated vascular calcification [84, 85]. Sclerostin antibody
treatment has demonstrated efficacy and superiority compared to other
anabolic treatments for increasing bone formation in both preclinical and
clinical settings. Accordingly, it has been suggested that sclerostin antibody
treatment is set to achieve market approval by 2017 and aggressively compete
as the gold standard for osteoporotic treatment by 2021 [86]. Moreover,
some studies suggested that dual sclerostin-DKK1 antibody outperforms
monotherapy [87]. Of note, randomized trial with humanized monoclonal anti-
sclerostin antibody (romosozumab) in osteoporotic women with low bone
mineral density did not report remarkable cardiovascular side effects during
follow-up period. However, patients with severe renal impairment (eGFR < 30
ml/min) were excluded from the trial [86]. Clearly, additional research
is needed to better understand the complex interactions between bone
metabolism and vascular health and confirm the effectiveness and safety value
of pharmaceutical targeting of bone anti-anabolic factors in various clinical
settings. In addition, appropriately designed and powered studies are required
to assess the probable effects of the above treatments on vascular
pathophysiology and on hard clinical outcomes, including cardiovascular
morbidity and mortality.
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