Control of Bone Homeostasis by the Wnt Inhibitor Sclerostin
Curr Mol Bio Rep
Control of Bone Homeostasis by the Wnt Inhibitor Sclerostin
Meghan E. McGee-Lawrence 0
Mark W. Hamrick 0
0 Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University , Augusta, GA 30912 , USA
Wnt signaling is an important osteogenic pathway regulating skeletal development and maintenance, and sclerostin is a potent extracellular inhibitor of this process. New anabolic skeletal therapies are needed to treat osteoporosis in the aging population, and pre-clinical and clinical studies demonstrate that targeting sclerostin with neutralizing antibodies releases an inhibitory brake on osteogenic Wnt signaling, promoting new bone formation and suppressing bone resorption to ultimately increase net bone mass. In this article, we review recent evidence regarding the regulation of sclerostin production in vivo under normal and disease states and summarize recent findings regarding the efficacy, mechanism of action, and potential complications of sclerostintargeting therapies (i.e., sclerostin-neutralizing antibodies) in the treatment of skeletal disorders. While recent studies have revealed a great deal of information regarding sclerostin's biological effects and regulatory patterns, much remains to be learned about the role of this molecule in the skeleton and other body systems.
Sost; Wnt; Romosozumab; Osteogenesis; Osteoporosis; Bone formation
Osteoporosis is the most common bone disease in humans; 54
million Americans either presented with or were at risk for this
disorder in 2010 [
], and these numbers will grow
exponentially with the aging American population . The most
widely used osteoporosis treatments (e.g., anti-resorptive
bisphosphonates or RANKL-inhibiting denosumab) slow
bone loss, but they do not build new bone or counteract
ageinduced loss of osteoblastic differentiation potential from
progenitor cells [
]. Parathyroid hormone (PTH) therapy, in the
form of teriparatide, is the only FDA-approved agent that
stimulates new bone formation, and its clinical usage is
limited to an 18-month Banabolic window^ of efficacy [
Wnt signaling has long been recognized as an important
osteogenic pathway in the regulation of skeletal development
and regeneration. In canonical Wnt signaling, binding of Wnt
ligands to Frizzled and Lrp5/6 co-receptors stabilizes
β-catenin, allowing it to accumulate in the cytosol, translocate to the
nucleus, and upregulate expression of Wnt target genes,
resulting in stimulation of osteoblast progenitor proliferation
and differentiation. Sclerostin, encoded by the SOST gene, is
an extracellular inhibitor of the canonical Wnt pathway. This
predominant osteocyte-produced glycoprotein was identified
through genetic screening of patients with the sclerosing bone
disorders sclerosteosis and van Buchem’s disease, locating
genetic mutations in the SOST gene or its regulatory elements
that produced a high bone mass phenotype in affected patients
]. Sclerostin antagonizes Wnt signaling by binding to
Lrp4, 5, and 6 co-receptors [
], blocking the ability of
Wnt ligands to bind and stimulate downstream signaling.
Although primarily produced by osteocytes, sclerostin
expression has also been detected in other cells like aged osteoclasts
, calcifying vascular tissue [
], and synoviocytes
[14 ]. As an inhibitor of Wnt signaling, sclerostin suppresses
both osteoblastic differentiation and activity [
Additionally, sclerostin stimulates RANKL expression in
osteocytes, promoting osteoclastic bone resorption .
Accordingly, sclerostin-deficient mice develop high bone
mass resulting from an immense increase in osteoblastic bone
formation and smaller but significant decreases in osteoclastic
bone resorption [
In this article, we review recent evidence regarding the
regulation of sclerostin production in vivo under normal and
disease states and summarize recent findings regarding the
efficacy of sclerostin-targeting therapies (i.e.,
sclerostinneutralizing antibodies) in the treatment of skeletal disorders.
Regulation of Sclerostin Production
As a powerful inhibitor of osteoblastic bone formation,
sclerostin levels must be tightly regulated in the body.
Recent findings regarding physiological regulators of Sost
and sclerostin expression are summarized below. Although
excellent earlier literature exists on many of these topics, we
have made an effort to highlight the results of recent studies
(published within the past five years).
It has been known for over a decade that PTH treatment
suppresses sclerostin production by human and murine osteocytes
16, 20, 21
]. Several recent reports have confirmed this
phenomenon in vivo, demonstrating that serum sclerostin levels
are negatively correlated with PTH levels in non-diabetic
] and decline in response to an acute infusion of PTH
]. Additionally, Sost overexpression abrogates increases in
cortical and cancellous bone mass caused by constitutively
active PTH1R signaling [
]. Suppression of sclerostin by
PTH requires the presence of the Wnt receptor LRP6 [
and occurs, at least in part, through the nuclear accumulation
of histone deacetylase 5 (Hdac5). Hdac5, in turn, subsequently
inhibits myocyte enhancer factor 2 (MEF2)-dependent
stimulation of the Sost bone enhancer [
26 , 27
] (discussed in detail
Sex Steroids (Estrogen, Testosterone)
In general, the sex steroids appear to inhibit sclerostin
production, best evidenced by the fact that sclerostin
levels increase in the case of sex steroid deficiency
]. Estrogen treatment of postmenopausal women
decreases circulating sclerostin [
], but the role of
testosterone is more controversial. One study
demonstrated that treatment with estrogen, but not testosterone,
prevents increases in sclerostin levels following
induction of acute sex steroid deficiency [
serum sclerostin levels are negatively correlated with
testosterone in male human patients, and treatment of
human osteocytes with dihydrotestosterone (DHT)
reduces Sost expression in these cells, suggesting a
potentially important role for testosterone in the biology of
sclerostin regulation [
The S ost gene is positively regulated by
1α,25dihydroxyvitamin D (1,25D), as both Sost messenger
RNA (mRNA) and sclerostin protein are rapidly increased
in response to 1,25D treatment in osteocyte-differentiated
human SaOS2 cells [
]. While sclerostin expression
is not necessarily altered by vitamin D deficiency in
adults, sclerostin levels are suppressed in babies born
to vitamin D deficient as compared to vitamin
Dsufficient mothers . However, the role of vitamin
D in Sost regulation is not completely clear, as
conflicting evidence exists. For example, murine Sost gene
expression is suppressed by 1,25D treatment in IDG-SW3
cells near the end of the osteoblast-to-osteocyte
transition period (i.e., near the time when the cells are
considered mature osteocytes) [
Sostdeficient mice demonstrate increased serum levels of
1,25D, resulting, in part, from enhanced expression of
25-hydroxyvitamin D 1α-hydroxylase cytochrome P450
(cyp27B1) in the kidney [
]; this could represent a
compensatory mechanism driven by the absence of
circulating sclerostin in the knockout animals but more
likely reflects the drive for a positive mineral balance
to support increased bone formation in the
Bone is a mechanoresponsive tissue, demonstrating
hypertrophy in response to increased mechanical loading and
atrophy in response to disuse. Mechanical loading
suppresses sclerostin production both in vitro (e.g., fluid flow
loading of osteocytes) [
] and in vivo (e.g., ulnar axial
]), whereas disuse increases sclerostin
expression in vitro [
] and in vivo [
sclerostin suppression requires production of nitric oxide,
as inhibition of nitric oxide synthase prevents the fluid
flow-induced suppression of Sost expression [
Administration of sclerostin-neutralizing antibodies
abrogates bone loss caused by disuse from hindlimb suspension
], spinal cord injury [
], and limb immobilization [
even when disuse is superimposed over a concurrent effect
of estrogen depletion from ovariectomy [
Surprisingly, both circulating and bone mRNA expression of
Sost are lower in osteoporotic as compared to healthy women
], despite the fact that sclerostin suppresses bone
formation. Subsequent analysis of this phenomenon revealed that
the Sost promoter is more methylated in patients with
established osteoporosis as compared to healthy controls,
suggesting that methylation to reduce Sost gene expression could
be a protective mechanism triggered to help reduce inhibition
of Wnt signaling and promote bone formation in osteoporotic
Beyond methylation, other epigenetic mechanisms may
also influence Sost production. Knockdown of Hdac5 increases
Sost expression, and overexpression of Hdac5 suppresses Sost
expression in osteocytes, and Hdac5-deficient mice show
increased expression of Sost and lower Wnt activity. This effect
occurs through modulation of the Mef2c transcription factor.
Sost expression is increased via binding of the transcription
factor Mef2c to a distal enhancer region (ECR5) [
Mef2C binding at this location is enhanced in the case of
Hdac5 deficiency [
Sclerostin Levels in Human Disease
Many diseases are intertwined with skeletal biology, causing
loss of bone mass secondary to organ dysfunction elsewhere
in the body. Recently, it has emerged that some of these
skeletal phenotypes may be linked with altered circulating levels
of sclerostin, as discussed below.
Diabetes mellitus is associated with increased risk of bone
], and patients may present with reduced bone
turnover, suggesting a potential regulatory role for sclerostin
in this phenotype . Recent reports indicate that circulating
sclerostin levels are increased in both type 1 and type 2
diabetic patients as compared to healthy controls [
although levels are not different between type 1 and type 2
diabetic patients . This increase likely begins in the
prediabetic phase when insulin resistance develops, as sclerostin
levels are increased in patients with impaired glucose
regulation (prior to onset of overt diabetes) as compared to
normoglycemic controls and are positively correlated with
homeostatic model assessment of insulin resistance (HOMA-IR)
]. In patients with type 2 diabetes, sclerostin levels are
elevated in patients presenting with fragility fractures
compared with non-fractured diabetic controls [
], and higher
sclerostin levels are associated with an increased risk of
vertebral fractures independent of BMD [
], supporting a role for
sclerostin in the fracture-prone phenotype of diabetic patients.
In contrast to this finding, one study revealed that type 1
diabetes patients with the highest tertile of circulating sclerostin
levels had decreased risk of fracture; the biological explanation
for this confounding observation is not yet known [
Renal osteodystrophy is a common complication of chronic
kidney disease, and the most common type of osteodystrophy
in end-stage renal disease is one with low turnover [
Sclerostin levels are increased in patients with chronic kidney
disease (CKD) both pre- and post-dialysis [
12, 54, 55
compared to healthy controls, with the highest expression
occurring at early stages of the disease [
]. At least one study
suggests that these high levels of sclerostin are inversely
correlated with bone formation rates, potentially contributing to
renal osteodystrophy in this patient population [
circulating sclerostin levels in patients with kidney disease are
rescued by renal transplantation [
]. Interestingly, circulating
sclerostin levels are increased in dialysis patients that develop
vascular calcifications as compared to dialysis patients free
from calcification complications [
]. Although sclerostin is
predominantly produced by osteocytes in vivo, its expression
is detected by immunohistochemistry and real-time PCR in
aortic valves developing calcification as compared to
noncalcified valves [
], suggesting that sclerostin could play a
role in the biomineralization of extraskeletal tissues.
Serum sclerostin levels appear to increase the case of liver
dysfunction. Several recent reports indicate that sclerostin
levels are elevated in patients with cirrhosis as compared to
healthy controls [
]. The mechanism for the increased
sclerostin in cirrhotic patients is not yet known, but
proposed contributing factors have included increased
retention secondary to liver dysfunction and altered expression
of sex steroids [
Human Immunodeficiency Virus
Patients infected with human immunodeficiency virus (HIV)
often develop low bone mass and subsequent fragility
fractures . It was recently reported that sclerostin levels are
suppressed in HIV infected as compared to healthy controls
for a small cohort of adult patients (33 HIV, 63 controls) .
These findings are supported by a second study suggesting
reduced sclerostin levels in HIV-infected youths and
adolescents as compared to healthy controls . As sclerostin
levels were not correlated with bone mineral density in this
population, these results raise the possibility that immune
function or systemic inflammation could regulate serum
sclerostin in HIV-affected patients .
Sclerostin Inhibition as an Anabolic Skeletal
Given the paucity of FDA-approved anabolic skeletal
therapies presently on the market, inhibition of sclerostin activity is
an attractive target for new osteogenic drug development. The
application of sclerostin-neutralizing antibodies (Scl-Abs) for
increasing bone mass has been under investigation at least
since 2009, when short-term administration of Scl-Ab therapy
was shown to improve bone formation, mass, and strength in
an ovariectomized rat model of osteoporosis . Below, we
summarize recent findings from animal and human studies
continuing to pursue this goal and discuss some potential
complications that could arise from use of Scl-Ab treatments.
Many recent animal studies have focused on better
understanding Scl-Ab’s mechanism of action, revealing novel
effects on bone formation and bone resorption. Whereas
bisphosphonate therapies primarily decrease bone resorption
and teriparatide administration stimulates increased bone
remodeling, Scl-Ab treatments increase bone mass by
promoting modeling-based bone formation and simultaneously
reducing bone resorption while extending the bone formation
period at modeling and remodeling sites . In cortical bone,
Scl-Ab promotes both periosteal and endocortical bone
formations, leading to a net increase in bone mass [67, 68].
Although Scl-Ab’s ability to stimulate bone formation in vivo
is limited to the early phases of treatment, its ability to suppress
bone resorption is sustained for a much greater length of time
[67, 69, 70]. Osteoblasts, bone lining cells, and osteocytes
collected by laser capture microdissection from Scl-Ab-treated
ovariectomized rats show upregulated expression of canonical
Wnt targets and genes related to matrix synthesis and
mineralization, as would be expected, but surprisingly show no
alteration in expression of genes related to osteoclastogenesis (e.g.,
RANKL) , even though sclerostin itself promotes RANKL
expression in osteocytes [
In humans, two Scl-Ab therapies are at various stages of
clinical development as treatments for post-menopausal
osteoporosis: romosozumab, developed by Amgen/UCB, and
blosozumab, developed by Eli Lilly. Results from phase II
trials of romosozumab were published in 2014, demonstrating
that all tested dose levels of romosozumab increase bone
mineral density at the lumbar spine, total hip, and femoral neck as
compared against placebo treatment [72 ]. Moreover, high
doses of romosozumab (210 mg, delivered monthly) increase
bone mineral density at each of these sites to a greater degree
than treatment with the anti-resorptive bisphosphonate
alendronate or the anabolic agent teriparatide [72 ].
Preliminary results from a much larger phase III trial of
romosozumab were presented in April of 2016, demonstrating
that 12 months of treatment with romosozumab increases
bone mineral density at the total hip and lumbar spine and
estimated bone strength at the hip by a greater amount than
teriparatide in osteoporotic postmenopausal women .
With regard to fracture prevention, recent reports
summarizing phase III results indicate that romosozumab reduces the
incidence of new vertebral fractures and clinical fractures in
postmenopausal women with osteoporosis.
Phase II trials of blosozumab were published in 2015,
demonstrating that 12 months of treatment with blosozumab
dosedependently increases bone mineral density at the lumbar
spine, femoral neck, and total hip as compared with placebo
treatment [74 ]. Bone mass gained with blosozumab treatment
appears to be maintained, as bone mineral density at the
lumbar spine and total hip remains greater in blosozumab treated
as compared to placebo-treated postmenopausal women [75 ].
Regarding other forms of osteoporosis, clinical trials to
investigate the efficacy of romosozumab to combat
agerelated osteoporosis in men are ongoing [
76 , 77
] but have
not yet been reported for blosozumab. Notably, circulating
sclerostin levels increase with age in humans, although bone
mRNA levels of SOST are not increased with age, suggesting
that extraskeletal production of sclerostin may contribute to
these aging-related changes . Scl-Ab therapies have also
proved efficacious for abrogating bone loss in other
osteoporosis models including glucocorticoid- and disuse-induced
osteoporosis. For example, administration of Scl-Ab therapy
prevents prednisolone-induced bone loss in mice [
blocks disuse-induced bone loss after spinal cord injury in
animal models [
40 , 80
Osteogenesis imperfecta (OI) is a genetic disorder caused
by mutation in type 1 collagen, the major organic
component of bone, resulting in a fragile skeleton. Anti-resorptive
bisphosphonates have shown some efficacy at preventing
fractures in this patient population [
], but Scl-Ab
therapies are being considered as new therapeutic
approaches to increase bone mass and prevent fractures in
OI patients. Although sclerostin antibody treatment cannot
rescue the genetic defect in collagen structure, recent
evidence from murine studies indicates that Scl-Ab treatments
increase whole bone mechanical strength in the skeleton of
OI mouse models , through an increase in overall bone
mass and altered bone matrix chemistry (e.g., mineral to
matrix ratio) [
]. This rescue appears to be effective with
models of both dominant mild OI (Brtl/+ mice) [
recessive OI (Crap-/- mice) . However, Scl-Ab
treatment was unable to improve bone strength in a mouse
model of dominant severe OI (Col1a1Jrt/+ mice) [
suggesting that efficacy of this therapy may be limited to particular
OI patient populations.
Sclerostin-deficient mice demonstrate enhanced skeletal
healing as compared to wild-type mice [
]. From a
translational perspective, it is more interesting to ask whether
systemic administration of a Scl-Ab would enhance fracture
repair. Animal studies seem promising, as both stabilized bone
] and closed fractures [
] heal more
rapidly with Scl-Ab administration. Despite success in these
animal models, manufactures of romosozumab abandoned
efforts to develop this treatment as a fracture-healing therapeutic
agent; preliminary data from phase II studies suggest that
treated patients do not demonstrate enhanced time to
radiological healing [
]. Thus, sclerostin antibody therapy may be
more effective at preventing the onset of new fractures as
compared to promoting enhanced healing of existing fractures.
Potential Issues with Anti-Sclerostin Therapies
Despite widespread enthusiasm for developing Scl-Ab
therapies as osteogenic agents, concerns have emerged regarding
potential side effects. In a recent study, researchers identified
that sclerostin is specifically expressed in synovial tissues of
patients with rheumatoid arthritis (RA), and subsequent
animal studies suggested that expression plays a protective role in
the body. Specifically, when mice lacking sclerostin are
crossed onto the background of a TNF-dependent RA model
(human TNF-α transgenic mice), the double-mutant animals
demonstrate enhanced joint inflammation and damage to the
cartilage and bone [
]. This suggests that Scl-Ab treatments
could be contraindicated in patients with TNF-dependent
arthritis. However, these negative effects were not seen in
nonTNF-dependent RA models, and it has also been recently
shown that Scl-Ab treatment of human TNF transgenic mice
prevents bone and cartilage erosion associated with RA
without exacerbating inflammatory metrics like paw swelling and
grip strength [
]. Conflicting conclusions between these
studies have not yet been reconciled.
New anabolic skeletal therapies are needed to treat
osteoporosis in the aging population. Pre-clinical and clinical studies
demonstrate that targeting sclerostin with neutralizing
antibodies releases an inhibitory brake on osteogenic Wnt
signaling, promoting new bone formation and suppressing bone
resorption to ultimately increase net bone mass. While recent
studies have revealed a great deal of information regarding
sclerostin’s biological effects and regulatory patterns, much
remains to be learned about the role of this molecule in the
skeleton and other body systems.
Acknowledgments Funding to MWH is provided by the National
Institute on Aging (NIA AG036675), and funding to MEML is provided
by the American Diabetes Association (1-16-JDF-062).
Compliance with Ethical Standards
Conflict of Interest Meghan E. McGee-Lawrence and Mark W.
Hamrick declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Papers of particular interest, published recently, have been
Of major importance
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