Role of sclerostin in the pathogenesis of chronic kidney disease-mineral bone disorder
Asamiya et al. Renal Replacement Therapy
Role of sclerostin in the pathogenesis of chronic kidney disease-mineral bone disorder
Yukari Asamiya 0
Ken Tsuchiya 0
Kosaku Nitta 0
0 Department of Medicine, Kidney Center, Tokyo Women's Medical University , 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666 , Japan
Sclerostin is a 190-amino-acid glycoprotein that is mainly secreted by osteocytes, and it decreases bone formation by inhibiting the terminal differentiation of osteoblasts and promoting their apoptosis. Sclerostin blocks the Wnt signaling pathway in osteoblasts by binding to low-density lipoprotein receptor-related protein 5/6 (LRP-5/6) receptors. We reviewed the literature detailing the role of sclerostin in the pathogenesis of chronic kidney disease-bone mineral disorder (CKD-MBD). Increased serum sclerostin levels may be correlated with increased serum levels of phosphate and fibroblast growth factor 23 (FGF23) in hemodialysis patients with relatively low parathyroid hormone levels. Decreased Wnt/β-catenin signaling occurs regardless of the overall changes in bone formation rates, suggesting that a reduction in the anabolic response may be a common feature of renal bone disorders; however, additional mechanisms may contribute to the diversity of osteodystrophy phenotypes. Recent clinical studies demonstrated that treatment with anti-sclerostin antibodies improved bone quality in the context of low but not high turnover renal osteodystrophy. Sclerostin also appears in the circulation, suggesting that it plays additional roles outside the skeleton under normal conditions and in disease states. The serum sclerostin levels in CKD patients are several times higher than in healthy subjects. Recent data suggest that the higher serum sclerostin levels are associated with increased fracture rates, but the relationship between sclerostin and cardiovascular disease is unclear. CKD stage-specific epidemiologic studies are needed to assess whether sclerostin elevations affect comorbidities associated with CKD-MBD.
CKD-MBD; Sclerostin; Osteocyte; Renal osteodystrophy; Wnt signaling
Sclerostin is a 190-residue secreted glycoprotein that is
predicted to contain a cysteine-knot motif and is a
member of the DAN/Cerberus protein family [
] (Fig. 1). In
patients with the rare inherited bone disorder,
sclerosteosis, which is characterized by exceptionally high bone
], have recently been found to be homozygous
for a defective sclerostin gene (SOST) [
], and a
similar high bone mass phenotype has been reported in
sclerostin knock-out mice . Sclerostin null mice have
very high bone mass, and conversely, severe osteopenia
occurs in transgenic mice overexpressing sclerostin in
]. Sclerostin is secreted by osteocytes and
has been shown to down-regulate the synthesis of
several bone formation markers by osteogenic cells [
thereby indicating the importance of sclerostin in the
regulation of bone formation.
Chronic kidney disease-mineral bone disorder
(CKDMBD) is defined by abnormalities in mineral and
hormone metabolism that lead to declining bone health and
soft tissue calcification [
]. Previous studies have
shown that these changes are associated with increased
fracture rates coupled with pathologic changes in the
cardiovascular system, including reduced vascular wall
elasticity, vascular calcification, and left ventricular
The specialized morphology of osteocytes allows them
to function effectively the balance between osteoblast
and osteoclast activity and regulate systemic mineral
metabolism. Osteocytes are the primary sites of
production of several factors important to bone and mineral
metabolism, including fibroblast growth factor 23
(FGF23) and sclerostin, which are considered the key
signal transduction molecules that function as negative
regulators of the Wnt/β-catenin pathway in bone. This
review describes the potential role of sclerostin in the
pathogenesis of CKD-MBD.
Wnt/β-catenin signaling and sclerostin
Wnt/β-catenin signaling plays a key role in various
biological processes, including cell proliferation, cell
migration, and differentiation [
]. The canonical Wnt
pathway involves interactions between several Wnt
ligands and their cognate receptors and co-receptors.
Wnt proteins are a family of highly conserved secreted
signaling molecules that regulate cell-to-cell
interactions during embryogenesis. As shown in Fig. 2, Wnt
ligands bind to cell surface receptor complexes that are
comprised of Frizzled and low-density lipoprotein
receptor-related protein (LRP) family members [
Only unphosphorylated β-catenin can translocate into
the nucleus and modulate target gene transcription
(Fig. 2a). In the presence of the soluble Wnt inhibitor
sclerostin, Wnt ligands are blocked from binding the
LRP-5/6-Frizzled receptor complex (Fig. 2b). Since Wnt
signaling encompasses vascular development and
endothelial cell specification as well as regulation of bone
modeling and remodeling, it appears prototypic for the
crosstalk within the bone-vascular axis [
addition to being dependent on the local expression of
specialized Wnt ligands, regulation of the canonical
Wnt pathway is dependent on the relative expression
of inhibitors that bind to either Wnts themselves
(Frizzled-related proteins, FRPs) or to one of the LRP
co-receptors, such as sclerostin or Dickkopf-related
protein 1 (Dkk1).
Role of sclerostin in bone metabolism
Sclerostin is mainly secreted by osteocytes, and it
decreases bone formation by inhibiting the terminal
differentiation of osteoblasts and promoting their apoptosis.
Sclerostin blocks Wnt signaling pathway in osteoblasts
by binding to LRP-5/6 receptors [
]. Osteocytes act as
mechanosensors, and they initiate and regulate
osteoclastogenesis by producing receptor activator of nuclear
factor-κB ligand (RANKL) and its decoy receptor
osteoprotegerin (OPG) (Fig. 3) [
]. Osteocytes also
regulate bone formation via the Wnt signaling pathway by
secreting sclerostin and Dkk1 . Sclerostin and Dkk1
bind to LRP-5/6 as Wnt co-receptors and they prevent
Wnt protein binding to secreted FRPs and its
coreceptors, an essential step for Wnt signaling [
Downstream actions of Wnt signaling result in
intracellular production of β-catenin, which regulates
transcription. Wnt signaling and bone morphogenetic protein are
involved in osteoblastogenesis and bone formation [
Sclerostin is also expressed in several non-skeletal
tissues, especially in the vasculature, but whether this is a
cause or a consequence of vascular calcification is yet to
be determined [
Renal osteodystrophy and Wnt signaling
Renal osteodystrophy is a syndrome of bone disorders
showing from low to high bone turnover and is
associated with disturbances in calcium and phosphorus
homeostasis in association with hyperparathyroidism
]. Parathyroid hormone (PTH) is known to bind
directly to cells of the osteoblast/osteocyte lineage and
promote increased RANKL expression, which leads to
osteoclast activation. The mechanism of the
predominant catabolic activity of sustained increased PTH
levels is consistent with the results of studies of the
effect of PTH therapy. The effect of intermittent PTH
administration is transient, because RANKL actions
are balanced by the subsequent rising levels of its
Canonical Wnt pathway
Sclerostin: mode of action
antagonist, OPG, thus accounting for the short burst
of osteoclast activity.
The transient activation of osteoclast activity leads to
increased osteoblast activity which triggers the classic
bone anabolic PTH response [
]. In contrast, catabolic
activity is observed when high PTH concentrations are
sustained, such as during continuous PTH therapy and
in pathologic hyperparathyroidism, because RANKL
expression remains high. The differential regulation of the
RANKL/OPG ratio by PTH appears to occur via
crosstalk with the Wnt/β-catenin pathway [
]. The PTH/
PTH1R receptor complex has been shown to directly
bind and phosphorylate the Wnt co-receptor LRP-6 in a
cAMP-dependent manner, thereby promoting β-catenin
stabilization in the absence of Wnt binding [
effect on β-catenin explains its effect on sclerostin,
because sclerostin down-regulation is a classic target of
β-catenin-controlled transcription. Taken together, the
mechanism of high bone turnover via a PTH-dependent
effect on the β-catenin pathway has been clearly
A recent study by Moe et al. assessed the effects of
anti-sclerostin in normal animals relative to a slow
progressing model of CKD-MBD with imposed low or
high PTH levels [
]. Antibody treatment had no
influence on bone health in CKD animals with high
PTH and elevated bone turnover and cortical porosity.
However, the antibody improved trabecular bone
volume and mineralization in CKD animals with low
PTH values that had bone defects associated with low
bone formation. These results correlated with a
reduction in bone expression of inactive phosphorylated
βcatenin, confirming its ability to restore Wnt/β-catenin
signaling. Bone strength was unchanged in CKD animals
with low PTH. In normal animals, the antibody treatment
improved bone volume, cortical geometry, and
biomechanical properties. The failure of the antibody to improve
bone strength in the context of CKD suggests that while
β-catenin contributes to bone disease, restoration of Wnt
binding to the receptor may not be sufficient to overcome
all bone changes associated with low bone turnover
osteodystrophy and that additional mechanisms may contribute
to the underlying defects in CKD.
A cross-sectional study of 60 dialysis patients showed
that their serum sclerostin levels were inversely
correlated with the patients’ bone formation rates [
subsequent prospective study of 81 dialysis patients found
that higher sclerostin serum concentrations predicted
greater loss of bone mass over a 1-year period [
These findings are consistent with the hypothesis that,
as would be expected of a negative regulator of bone
formation, higher serum sclerostin levels promote low
bone turnover, which leads to loss of bone mass over
time. Additional studies are needed to determine
whether differential serum sclerostin levels are
associated with bone disease associated with high versus low
Serum sclerostin levels in CKD
The molecular size of sclerostin is approximately
22.5 kDa, and the majority of sclerostin is likely to be
filtered through glomeruli and reabsorbed by renal tubular
cells in a normal kidney. McNulty et al. reported firstly
two enzyme-linked immunoassays, one for measuring
serum sclerostin levels and the other for measuring
plasma sclerostin levels [
], and the concentrations of
sclerostin in serum and in plasma were different when
determined by the two assays. A comparative study of
the two assays showed that the plasma sclerostin levels
were 30 % higher than the serum sclerostin levels and
that the intra-assay and inter-assay coefficients of
variance were less than 10 % and less than 20 %, respectively
]. As shown in Table 1, serum sclerostin levels under
various physiological and pathological conditions have
been listed in a review article [
Serum sclerostin levels were significantly correlated
with age and were higher in male than female patients
with stage 3b and 4 CKD [
]. The high serum sclerostin
levels of CKD patients are likely to be dependent on
accumulation of sclerostin in the serum due to a decline
in glomerular filtration rate (GFR) and/or increased
sclerostin production by osteocytes. There is a
controversy for the mechanism involved in increased serum
sclerostin levels in CKD patients. For example, Cejka
et al. reported that renal elimination of sclerostin
increased regardless of decline in renal function and
urinary sclerostin excretion increased with declining GFR
]. Furthermore, increased extraskeletal production of
sclerostin may be one of the causes of its high serum
levels. For example, Roforth et al. reported that bone
mRNA levels did not increase in older people regardless
of their high serum sclerostin levels [
sclerostin levels have been found to be increased in
several cohorts of CKD patients. Cejka et al. were the first
to report finding increased serum sclerostin levels in a
cross-sectional study of dialysis patients [
], and their
finding has been validated by other studies in ESRD
23, 29, 30, 38–40
]. Pelletier et al. reported that
higher serum sclerostin levels were starting at CKD stage
3 . However, the degree to which serum sclerostin
levels reflect changes in expression versus accumulation
in individuals with impaired renal function is not fully
understood. A previous study examining the local
expression of sclerostin across stages of CKD revealed that
Dkk 1 SOST
Direct effect on osteoblast, osteocyte number, and on Wnt signaling.
Serum sclerostin levels increase with age, but bone marrow sclerostin mRNA is not increased in
Likely due to higher bone mass (osteocyte number); lower in premenopausal women because
of estrogen effect.
Lack of inhibitory effect of estrogen or decreased bone formation leading to low osteocyte number.
In patients with anorexia nervosa, sclerostin does not decrease with estrogen therapy.
Limited data; one study each in normal and dialysis patients; confounding by PTH is likely.
Direct effect of estrogen and possibly SERMs on osteoblast/osteocyte number and function.
Increased in prostate cancer patients and during androgen deprivation therapy.
Sclerostin levels were higher in obese patient and correlated with leptin and PTH levels.
IGF is obligatory to the anabolic action of PTH; may be for osteocyte function and sclerostin as well.
Lower levels compared with controls in untreated patients and normalize after
highest osteocyte expression occurred at initial stages of
the disease [
]. Although this study examined the
number of sclerostin-positive osteocytes rather than absolute
protein levels, the resulting data suggest that sclerostin
accumulation in the serum is at least partially due to
increased osteocyte production. Moreover, the rapid
restoration of serum sclerostin to the normal range
posttransplant suggests that decreased renal clearance
may also be responsible for accumulation at least in late
Delanaye et al. reported finding that plasma sclerostin
levels in hemodialysis patients were positively associated
with their phosphate levels and negatively associated
with their PTH levels [
]. We have recently reported an
increased serum sclerostin levels (Fig. 4) and that serum
sclerostin were closely associated with serum phosphate
and FGF23 levels and treatment with vitamin D in
hemodialysis patients with low serum PTH levels [
Further study will be necessary to determine whether
these relationships between serum sclerostin levels and
PTH and FGF23 levels are present in dialysis patients
with spontaneously low PTH levels who are not being
treated with vitamin D.
Association between sclerostin and vascular calcification
Vascular calcification results from a phenotypic conversion
of vascular smooth muscle cells into an osteoblast-like
] that involves induction of an osteoblast
transcriptional activation of osteocyte-specific proteins,
such as FGF23 and sclerostin, via a Wnt-dependent
]. The characteristics of negative regulators of
Wnt signaling can therefore be expected to prevent
osteoblast maturation and the progression of
Sclerostin has been implicated in the pathogenesis of
vascular calcification in postmenopausal women [
Several inhibitors of Wnt signaling, including FRPs,
Dkk1, and sclerostin, are over-expressed in arterial walls,
aortic valves, and atherosclerotic lesions and during
vascular smooth muscle cell calcification [
]. A post
hoc analysis of the data of 100 prevalent hemodialysis
patients monitored over a 2-year period demonstrated
an association between higher serum sclerostin levels
and improved survival . A prospective cohort study
of 673 incident dialysis patients also found that high
serum sclerostin levels were associated with lower
cardiovascular mortality over an 18-month period, but the
association was less pronounced after 4 years [
the other hand, the potential protective effect of
sclerostin against cardiovascular disease is in clear conflict with
the results of the preclinical studies reported above
showing that antibodies to the Wnt antagonist Dkk1
ameliorated cardiovascular calcification against a
background of low bone turnover [
]. However, elevated
DKK1 level and decreased vascular klotho are not
usually observed in patients with early CKD stage, and the
result is not likely to be generalized.
Taken together, the above findings are consistent
with a hypothesis that increased serum Wnt
antagonist levels induce low bone turnover, thereby indirectly
increasing the propensity for vascular calcification. In
suspect of this hypothesis, the serum sclerostin levels
of hemodialysis patients have been found to be
positively associated with coronary and aortic valve
calcifications, and higher expression of sclerostin has been
observed close to calcified areas in explanted aortic valves
from dialysis patients [
]. Moreover, the results of a
recent study of prevalent hemodialysis patients indicated
that serum sclerostin is an independent predictor of
An increase in the serum level of the Wnt antagonist
sclerostin and repression of Wnt/β-catenin signaling are
among the growing list of disturbances linked to
CKDMBD progression. These disturbances are consistent
with a general reduction in bone anabolism that appears
to be independent of osteoclast activity, suggesting that
osteoblast activity is insufficient even in the context of
the increased osteoclast activity observed in some cases
of renal osteodystrophy, which in turn, suggests that
additional mechanisms contribute to the diversity of the
skeletal defects in CKD.
The conflicting data regarding potential relationships
between increased serum sclerostin levels and both
cardiovascular disease and mortality underscore the need
for further study. Extended investigation of pathologic
mechanisms and pathways in clinical biopsy specimens
and in clinical samples, across various tissues and CKD
stages, will be helpful in generating additional
hypotheses. However, additional longitudinal assessments in
large patient populations will undoubtedly be of benefit
in achieving a complete understanding of sclerostin’s
impact on clinically relevant endpoints. The current
information regarding sclerostin and its role in CKD-MBD
provides yet another example of the critical need to take
a system biology approach to understanding the full
import of changes associated with the pathogenesis of
The authors have no conflicts of interest to declare.
YA planned the review, searched the literature, and prepared the article. KT
searched the literature and assisted in writing the article. KN planned the
context of this article and assisted in writing the article. All authors read and
approved the final manuscript.
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