Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

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doi: 10.17219/acem/169567

Publication type: review

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Kocełak P, Puzianowska-Kuźnicka M, Olszanecka-Glinianowicz M, Chudek J. Wnt signaling pathway and sclerostin in the development of atherosclerosis and vascular calcification [published online as ahead of print on September 7, 2023]. Adv Clin Exp Med. 2024. doi:10.17219/acem/169567

Wnt signaling pathway and sclerostin in the development of atherosclerosis and vascular calcification

Piotr Kocełak1,A,B,C,D, Monika Puzianowska-Kuźnicka2,3,C,E, Magdalena Olszanecka-Glinianowicz4,A,E,F, Jerzy Chudek5,A,C,F

1 Pathophysiology Unit, Department of Pathophysiology, Faculty of Medical Sciences, Medical University of Silesia, Katowice, Poland

2 Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, Warsaw, Poland

3 Department of Human Epigenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland

4 Health Promotion and Obesity Management Unit, Department of Pathophysiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Poland

5 Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Poland

Graphical abstract

Graphical abstracts


Atherosclerosis is a complex process involving endothelial dysfunction, vascular inflammation, vascular smooth muscle cell (VSMC) proliferation, angiogenesis, and calcification. One of the pathomechanisms of atherosclerosis is the upregulation of Wnt signaling. This study aimed to summarize the current knowledge regarding the role of Wnt signaling and sclerostin in atherosclerosis, vascular calcification, aneurysms, and mortality based on the PubMed database. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation and identified 160 papers that were included in this systematic review.

The published data highlight that the upregulation of Wnt components facilitates the initiation and progression of atherosclerosis, arterial remodeling, VSMCs proliferation and phenotypic transition to the osteoblastic lineage in the arterial wall. This results in protein secretion, cell migration, calcification, fibrosis and aneurysm formation. The transformation of VSMCs into osteoblast-like cells that is observed in atherosclerosis results in sclerostin expression inhibiting the Wnt pathway. Furthermore, it was shown that sclerostin, expressed in atherosclerotic plaques, inhibits aneurysm formation in a mouse model. However, in humans, while the antisclerostin antibody romosozumab inhibits bone resorption, biochemical parameters of endothelial activation and inflammation are not affected, and the incidence of aneurysms is not increased. It was suggested that detecting sclerostin in the calcified aortic atherosclerotic plaques reflects a defense mechanism against Wnt activation and inhibition of atherosclerosis, although this has only been shown in animal models. Moreover, an increased number of vascular cells converted to osteogenic phenotypes results in increased plasma sclerostin concentrations. Therefore, plasma sclerostin derived from bone limits its importance as a global marker of vascular calcification.

Key words: atherosclerosis, aneurysm, cardiovascular disease, sclerostin, WNT-signaling


Cardiovascular disease (CVD) is one of the most common causes of mortality worldwide,1 the most frequent form of which is coronary artery disease (CAD) associated with atherosclerosis, and its acute form (myocardial infarction) is responsible for most deaths. Atherosclerosis is a complex process that consists of several pathological traits, including endothelial dysfunction, vascular inflammation, vascular smooth muscle cell (VSMC) proliferation, plaque angiogenesis, and calcification.2, 3 Moreover, all these processes are associated with the Wnt signaling pathway.2, 4

The process of arterial calcification stems from the transformation of VSMCs localized in the intima-media into osteoblast-like cells,5, 6 thereby switching functions from contractile to synthetic. The shift in VSMC phenotype is primarily related to runt-related transcription factor 2 (RUNX2) expression regulated by the Wnt pathway.6, 7 The increase in mechanical load within arteries likely releases proteins to strengthen the action on the RUNX2 factor and facilitates the action of the Wnt-enhancing calcification.8 This process can be driven by soft tissue injury, resulting in the disruption of homeostasis and the initiation of bone matrix development, leading to ectopic calcification and mineralization of soft tissues.9

The main functions of Wnt signaling are the regulation of cell migration and polarity, organogenesis, fate determination, and proliferation of cells during embryonic development. Wnt signaling is also involved in the proliferation of stem cells into progenitor cells, which can subsequently differentiate into several cell types, including cardiac muscle, VSMC and endothelial cells. Therefore, the Wnt pathway is crucial during embryonic development and plays a role in the homeostasis of the adult organism. Moreover, the Wnt pathway is ubiquitous and controls many fundamental cellular processes, including osteogenesis, integrating multiple receptors, growth factors and cellular connections to transcription factors that affect gene expression.4

Sclerostin (SOST), an inhibitor of bone formation and calcification secreted by osteocytes,10, 11 is also a soluble inhibitor of the Wnt canonical signaling pathway. Sclerostin is involved in bone tissue homeostasis, inhibits osteogenesis and calcification, and is a modulator of bone homeostasis.10, 11 Its mechanism of action is to bind the LRP5 receptors and disrupt the canonical Wnt pathway.

Numerous studies have reported the involvement of sclerostin in the development of atherosclerosis11, 12 and its complications,13, 14 including arterial stenosis,14 and clinical presentation in the form of ischemic heart disease,15 cerebral ischemia16, 17 and peripheral artery disease,18 but also more advanced complications such as vascular calcification19, 20, 21, 22 and aneurysm development.22 The results of some studies suggest that sclerostin could potentially play a positive role and inhibit the progression of atherosclerosis.23

Moreover, it has been shown that sclerostin may be locally produced in calcified tissue and may act as a counter mechanism against enhanced calcification in arterial beds. It seems that sclerostin may constitute the intermediary between bone homeostasis and the development of vessel calcification and atherosclerosis.


As the induction of calcification is an important element in atherosclerosis, we aimed to summarize the knowledge on the role of Wnt signaling and sclerostin in the development of atherosclerosis and vascular calcification.


Data on the role of Wnt signaling and sclerostin in the development of atherosclerosis, arterial aneurysm and mortality presented in the article are based on published studies available in the PubMed database. Our search was based on the keywords “Wnt signaling”, “sclerostin”, “atherosclerosis”, “vascular calcification”, “aneurysm”, and “cardiovascular mortality”, and we initially identified 652 articles. Following a review by 2 of the authors, 160 studies were included in the article. Duplicated articles, as well as papers without full-text availability, were excluded from the review. The review included a broad range of articles, from basic molecular studies to clinical outcome investigations. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram is presented in Figure 1.

The Wnt pathway: general overview

The ‘Wnt’ name comes from the combination of the Wingless segment polarity gene name in Drosophila and its vertebrate homolog int-1 (integrated). This highly conserved signaling pathway is activated by membrane receptors.24 The Wnt signaling pathway consists of at least 19 proteins and is involved in numerous biological processes, including embryonic development, organogenesis, stem cell development, cell proliferation, differentiation, migration and polarity, tissue homeostasis, and glucose and lipid metabolism.24, 25, 26, 27 Furthermore, Wnt signaling participates in bone formation, vascular and valvular calcification,2, 3, 19, 28, 29 and angiogenesis.30 In the process of angiogenesis, Wnt signaling regulates endothelial cell proliferation and survival,31 and proliferation, migration and survival of VSMCs via the Wnt/β-catenin pathway.2, 28, 29, 30

Alterations in Wnt signaling appear to be directly involved in the increase of cardiovascular risk. For example, in mouse models, mutations of the co-receptors of Frizzled (Fz), a receptor in the Wnt pathway (e.g., low-density lipoprotein receptor-related protein 6 (LRP6)), are associated with an increase in morphogenesis and differentiation of adipocytes,32 enhancement of monocyte adhesion to endothelial cells, the proliferation of VSMCs,30 vascular calcification,33 hypercholesterolemia and, consequently, hypertension, type 2 diabetes mellitus (T2DM) and premature CAD.34 The current literature also shows that enhanced Wnt signaling, due to gain-of-function mutations of all elements of this signaling pathway, is associated with alterations in vascular development.35, 36

The Wnt pathway: mechanism of action

The Wnt proteins secreted by epithelial cells bind to the extracellular domain of the Fz surface receptor family. The Wnt ligand and the Fz receptor require LRP5/6 as co-receptors for the transduction of the signal into the cells.24 Other ligands that can activate LRP5/6 receptors include parathormone (PTH)37 and G-protein-coupled ligands such as isoproterenol (β-mimetic), adenosine and glucagon.38 Furthermore, LRP5/6 are also co-receptors for a platelet-derived growth factor (PDGF) and the transforming growth factor-β (TGF-β) receptor.39 The complex of Wnt protein/Fz receptor with LRP5/6 co-receptors transduces the signal to cytoplasmic phosphoprotein Dishevelled (Dsh/Dvl). Moreover, Wnt signaling activates 3 different pathways: canonical, planar cell polarity (PCP) and the Wnt/Ca.24

The canonical pathway

The canonical pathway comprises Dsh signaling to protein complexes which, in the absence of Wnt ligands, promotes the ubiquitination and finally degradation of β-catenin,24 while the Wnt ligand and activation of the Fz-LRP5/6 receptor complex inhibits this degradation, resulting in the translocation of β-catenin from the cytoplasm into the nucleus. Finally, β-catenin interacts with T-cell factor (TCF)/lymphoid-enhancer binding factor (LEF), which activates the transcription of Wnt-related genes that encode cyclin D1, PPAR and c-Myc, all of which are responsible for cell growth, proliferation and survival.24

The non-canonical pathways

The non-canonical pathways comprise the PCP pathway, which regulates the cytoskeletal organization and cell polarization,24 and the Wnt/Ca pathway responsible for the regulation of cell movement and adhesion.24 In these pathways, the Wnt signal is mediated through Fz receptors independent from the LRP5/6 co-receptor. The co-receptors for this pathway are likely mediated through tyrosine-protein kinase transmembrane receptor (ROR2),40 neurotrophin-related protein 1 (NRH1),41 receptor tyrosine kinase (Ryk),42 and protein tyrosine kinase 7 (PTK).43

The transduction of the non-canonical signaling leads to the activation of cytoplasmic Dsh, which is similar to the activation of the canonical pathway, but the PCP pathway utilizes the PDZ and DEP domains of Dsh, and ultimately activates the small GTPases Rho and Rac.44 One branch of this pathway acts through Daam 1 (Dishevelled-associated activator of morphogenesis 1), which binds to the central PDZ domain of Dsh and activates Rho GTPase through WGEF (weak-similarity GEF).45 Active Rho GTPase can stimulate Rho-associated kinase (ROCK)46 and myosin,47 resulting in the modification of actin and cytoskeletal organization.

The other signaling branch depends on the C-terminal DEP domain of Dsh and stimulates Rac GTPase activity.48 Rac triggers c-Jun N-terminal kinase (JNK)49 in a Daam-independent manner. Both Rho and Rac GTPases can regulate transcription and alter cell organization and polarity.50

The 2nd arm of non-canonical Wnt signaling, the Wnt/Ca pathway, is responsible for an increase in intracellular calcium levels through trimeric G protein signaling.51, 52 Increased calcium stimulates calcium-sensitive kinases, including phospholipase C, and protein kinase C (PKC).53 Moreover, the Wnt/Ca pathway is thought to stimulate the canonical and PCP pathways54, 55 by utilizing the PDZ and DEP domains of the Dsh protein. However, in the non-canonical pathway, the Dsh protein is localized at the cell membrane and not in the cytoplasm as in the canonical Wnt signaling pathway.56 Finally, the Wnt/Ca pathway is essential in embryonic development, cell adhesion, tissue orientation, and organ formation.51

Numerous factors, such as secreted frizzled-related proteins (sFRPs)57 and Wnt inhibitory factor-1 (WIF-1),58 may inhibit the Wnt pathways by directly binding to Wnt and preventing its connection with the receptor. In addition, sclerostin59 and Dickkopf (Dkk) family members60 inhibit the transduction of the signal by binding to LRP5/6. The Wnt signaling pathways are highlighted in Figure 2.

Wnt signaling and bone formation

Wnt signaling participates in bone formation by increasing the transformation of mesenchymal stem cells (MSCs) to osteoblasts while inhibiting osteoclast differentiation.61, 62

Bone cells, including osteoblasts, osteocytes, chondrocytes and bone marrow cells, produce many Wnt ligands.63 In the mouse, these are secreted from osteoblasts in an autocrine manner and participate in their mineralization and maturation. Moreover, Wnt16 induces osteoprotegerin expression in osteoblasts via the Wnt-β-catenin pathway64 and inhibits osteoclasts formation independent from osteoprotegerin (OPG) action.65 Furthermore, the Wnt5a ligand involved in the non-canonical signaling pathway is responsible for osteoblast lineage formation from mesenchymal precursors and can inhibit adipocyte differentiation.66 Even though the receptor for Wnt5a is the tyrosine kinase orphan receptor 2 (Ror2), its action results in enhancement in LRP5/6, which activates β-catenin and enhances the expression of OPG, and promotes osteoblast differentiation.66

Wnt3a, a Wnt ligand in the canonical signaling pathway, inhibits calcitriol-induced, but not Rankl-induced osteoclast formation induced by OPG expression in osteoblasts.67 Moreover, Wnt16 secreted from osteoblasts inhibits human and mouse osteoclast formation by disrupting Rankl in a Wnt-independent manner.64 This is achieved through inhibiting Rankl-induced activation of NF-kB and calcitriol-induced mice osteoclast formation.68 Wnt4 is also expressed in osteoblasts and inhibits osteoclasts formation independently from the Wnt pathway by enhancing OPG expression.69

Wnt5a enhances LRP5/6 expression in osteoblasts and simultaneously promotes Wnt10b and activates the Wnt/β-catenin pathway to induce osteoclasts formation. The interplay between Wnt5a and Wnt16 may also regulate osteoclastogenesis and osteolysis, and it is known that Wnt5a mediates osteoclast formation by binding to and stimulating Ror-2 receptors.70 Conditions such as arthritis with a high level of Wnt5a may reverse the inhibitory effect of Wnt16 on osteoclast formation.66, 70

In summary, secreted Wnt signaling ligands regulate osteoblast and osteoclast differentiation, and their interplay defines the balance between bone formation and bone resorption. The surrounding environmental conditions determine the induction of different Wnt ligands and the regulation of bone homeostasis.

Wnt signaling and atherosclerosis

All aspects of Wnt signaling are closely associated with the initiation and progression of atherosclerosis.26, 30 The upregulation of Wnt signaling (increased expression of the components of Wnt signaling, including WNT5a, WNT5b and WNT11) was detected in human aortic calcified atherosclerotic lesions and related aneurysms.23, 71 Furthermore, shear stress appears to be the primary mechanism that triggers the upregulation of Wnt signaling.72 In addition, upregulated Wnt signaling affects endothelial cell proliferation and survival, enhances monocyte adhesion and transendothelial migration,3, 73 and results in dysregulation of proliferation and apoptosis of VSMCs.28 Wnt signaling participates in bone formation by increasing the transformation of MSCs to osteoblasts and inhibiting differentiation to osteoclasts.61, 62 Therefore, inappropriate activation of the Wnt signaling pathway may play a role in osteoblastic transition into the arterial wall74 and vascular calcification.30 It appears that the link between atherosclerosis and bone loss is mediated through the canonical Wnt signaling pathway.11

Atherosclerosis development is associated with the proliferation and migration of VSMCs and endothelial dysfunction.75 The canonical Wnt/β-catenin signaling pathway results in the upregulation of proliferation genes, such as cyclin D1 responsible for VSMCs proliferation.74 Some of the WNT family genes encoding proteins such as WNT174, 76 and WNT5a77 in VSMCs and macrophages from atherosclerotic plaques have been identified as the initiators of VSMCs proliferation and release of pro-inflammatory cytokines. Additionally, overexpression of Wnt inhibitors like sFRPs has been shown to constrain VSMC proliferation.76 In contrast, Wnt3a exerts an anti-inflammatory effect by modulating NFκB-related gene expression in a mouse model.78 Moreover, an increased DKK-1 level promotes pro-inflammatory cytokine release,79 and the Wnt co-receptor LRP5 is responsible for enhancing lipid uptake, transforming macrophages into foam cells, and macrophage migration through enhanced regulation of Wnt-related proteins such as osteopontin (OPN), bone morphogenetic protein 2 (BMP2), cyclin D1, c-jun, lymphoid enhancer factor 1 (LEF1), and β-catenin.80

The Wnt pathway regulates the expression of OPG and OPN associated with extracellular matrix mineralization.81 Osteopontin has pro-inflammatory properties82 and activates the proteolytic activity of metalloproteinases,83 while OPG expressed in endothelial cells and VSMCs84 plays a role in the pathogenesis of atherosclerosis and the progression of aortic aneurysms.85

Wnt signaling is also involved in the process of fibrogenesis through TGF-β activation.86 Pathological activation of the canonical Wnt pathway has been detected in pulmonary,87 dermal,88 renal,89 and myocardial infarction-related fibrosis,90 and in muscles of mice from a model of musculoskeletal dystrophy.91 The DKK proteins are thought to play a significant role in inhibiting the Wnt canonical pathway by either binding to the LRP5/6 receptor and its co-receptor Kremen-1/2, internalizing the receptor and facilitating its degradation, or by disrupting the interaction between WNT and the LRP5/6 and Fz co-receptor complex.92 In cultured human fibroblasts, TGF-β signaling led to lower DKK-1 expression, which in turn activated the Wnt pathway. Both lower expression of DKK-1 and the use of DKK-1-neutralizing antibodies resulted in aggravation of fibrosis, whereas overexpression of DKK-1 prevented the initiation of fibrosis in the skin obtained from patients with systemic sclerosis.91 Overexpression of Wnt proteins in fibroblasts has been detected in enhanced generalized dermal fibrosis mouse models.91 This evidence demonstrates that the interrelation of the TGF-β pathway and Wnt signaling plays a pivotal role in the pathogenesis of fibrosis.91

During atherosclerosis, fibrosis is present in the wall of the artery and heart valves. WNT5b and WNT11 proteins were detected in aortic valvular interstitial cells with extensive fibrosis, underscoring the role of the canonical Wnt pathway in the development and exacerbation of atherosclerosis in humans.71

Wnt signaling and vascular calcification

The involvement of Wnt signaling in physiological bone turnover may be the herald of calcification, as the process of calcifying smooth muscle cells resembles the process of osteogenesis. Vascular calcification is one of the most common locations of ectopic soft tissue calcification and represents the congregation of hydroxyapatite preferentially in the tunica media9 during diabetes and chronic kidney disease (CKD), and contributes to the development of hypertension and cardiovascular complications.93 The primary pathological process is that of the transition of mesenchymal VSMCs into a single-lineage osteogenic cell type.94 In the presence of calcified arterial plaques, a loss of elasticity increases the constant strain exerted on arteries resulting in VSMC proliferation and differentiation.6 In transformed VSMCs, osteogenic genes have been found, albeit their mRNA expression is significantly lower than in osteoblasts.95 Moreover, high plasma levels of calcium and phosphate initiate the process of calcium deposition in arteries by changing the phenotype of VSMCs and increasing the expression of osteogenic proteins.96, 97 The main regulatory mechanism involved in the process of calcification and plaque formation is the canonical Wnt signaling pathway.98 The target gene of the Wnt cascade is the transcription factor RUNX2 responsible for the phenotypic change of VSMC,7 osteoblast differentiation and initiation of calcification.24

The arterial Wnt signaling pathway is induced by hypercalcemia and hyperphosphatemia, RUNX2, BMP-2 and -4, and stress or injury, which results in the upregulation of Wnt-related genes.99 The Wnt signaling pathway induces vascular calcification by promoting the expression of genes responsible for VSMC differentiation like RUNX2 (osteogenic differentiation),100 VCAN (cell proliferation and migration due to vessel injury),101 OPG to inhibit osteoclast formation,102 and RANKL (responsible for the recruitment of osteoblast-like precursors).100

Wnt3a has been shown to activate β-catenin and RUNX2 expression, thereby increasing arterial calcium deposition and osteocalcin expression resulting in the promotion of VSMC calcification103 as well as migration by increased adherence to type 1 collagen fibrils.104 Moreover, Wnt7b plays a role in the development of neo-vasculature via the Wnt signaling pathway,105 while Wnt16 has been implicated in changing the phenotype of VSMCs from contractile to osteogenic lineage.106

Sclerostin: mechanism of action

Sclerostin, the product of the SOST gene107 and secreted by osteocytes,10 acts mainly in an autocrine and paracrine manner. The physiological role of sclerostin is the inhibition of bone formation and calcification,11 and it has been suggested that the serum concentration of sclerostin reflects the pool of mature osteocytes.107 Its expression was also detected in many other tissues, including the heart, lungs and cancers.108 The mechanisms of sclerostin action are summarized in Table 1.

Sclerostin is a soluble inhibitor of the canonical Wnt signaling pathway and therefore regulates the proliferation and differentiation of osteoblasts and bone formation.117 It antagonizes BMP signaling, thus stimulating osteoblast and osteocyte apoptosis.118, 119 The autocrine action of sclerostin also involves stimulating RANKL expression in osteocytes, thus supporting osteoclast activity and bone resorption.120 In addition, the paracrine action of sclerostin on osteoblasts and osteoclasts by the LRP5 receptor inhibits bone formation.121

Sclerostin signaling is modulated by numerous factors, including calcitriol, which facilitates its action by modulating the expression of LRP5/6, the sclerostin receptor. In addition, as shown in mice models, calcitriol enhances the expression of Dkk-1 and secretion of frizzled-related protein 2 (Sfrp2), which are antagonists of the Wnt signaling pathway.122 Other factors modulating the action of sclerostin are PTH,123 tumor necrosis factor alpha (TNF-α)110 and glucocorticoids.111

Thus, the physiological role of sclerostin in the regulation of bone mineralization is the inhibition of the canonical Wnt/β-catenin pathway via LRP5/6 binding109 It also enhances the degradation of β-catenin, resulting in the inhibition of osteoblast differentiation and proliferation.

As mentioned above, numerous studies have shown the essential role of the Wnt signaling pathway in vascular development and remodeling.30 An anti-calcification effect related to the inhibition of the Wnt pathway was demonstrated in carotid plaques and calcified aortas.112 Thus, the presence of sclerostin in human arteries is not unexpected.124 Some studies have also reported sclerostin and DKK-1 expression in calcified human aortas and carotid plaques.124

Sclerostin expression in VSMCs likely reflects their transition to osteoblast-like cells.112 This hypothesis is supported by a positive correlation between serum sclerostin concentration and the severity of aortic calcification.21, 125 In addition, it was shown that β-catenin activity is crucial in initiating VSMC proliferation and neointima formation, processes essential in arterial physiology. Reactive oxygen species (ROS) are among the factors that can enhance β-catenin activity.74 Sclerostin and DKK-1 inhibit the β-catenin-dependent Wnt signaling pathway, and therefore a high sclerostin level may indicate a defensive mechanism against enhanced Wnt pathway stimulation by ROS.33 The process of vascular calcification resembles that of bone morphogenesis.126 Wnt signaling mediates the differentiation of progenitor and VSMCs into an osteo/chondro phenotype.127 This was seen in cultured rat VSMCs, in which Dkk-1 acts as a potent inhibitor of the canonical Wnt signaling pathway reducing the expression of Runx2, an essential transcription factor for osteogenic differentiation.103 In human knee chondrocytes, the incubation with sclerostin resulted in a decrease of RUNX-2 mRNA.128 Therefore, both sclerostin and Dkk-1 proteins may neutralize the process of vascular calcification and modify arterial stiffness and arteriosclerotic plaque stability.129

Sclerostin and atherosclerosis

Interestingly, a higher sclerostin concentration was found in the media compared to the intima of atherosclerotic plaques of patients undergoing carotid endarterectomy, and a similar finding was demonstrated for VSMCs when compared to infiltrating macrophages.130 Sclerostin was also found in the aorta of patients undergoing aortic valve surgery and was upregulated in calcifying VSMCs and calcified valvular plaques.21 Serum sclerostin levels have been associated with the presence of thoracic aortic calcification (TAC), the severity of calcification, and sclerostin expression in the vessel wall.131 Numerous studies have shown associations between sclerostin levels and aortic or carotid plaques and vascular calcifications in patients with T2DM and CVD and in postmenopausal women.12, 132, 133 In addition, sclerostin levels were higher in elderly patients with peripheral arterial disease (PAD) than in patients with a normal value of the ankle-brachial index (ABI), and higher sclerostin levels were shown to be an independent predictor of PAD.18 Therefore, it seems that sclerostin may be considered a surrogate marker of vascular calcification, and may even be a surrogate of vascular disturbances in patients with CKD.134 Previous literature also suggests that increased sclerostin levels in VSMCs may protect against excessive vascular calcification in dialysis patients.133 However, this mechanism has limited efficacy.

The increased sclerostin concentrations observed during the course of atherosclerosis in a clinical setting seem to be ineffective in exerting protective anti-calcification effects in damaged vessels. Moreover, clinical studies show sex-related differences in sclerostin concentrations, which are higher in men, and in the frequency and course of CVD. However, even higher serum sclerostin concentrations in men do not prevent the occurrence and progression of atherosclerosis, suggesting that the levels of circulating sclerostin are not effective in inhibiting the pathological process in vessels.135

Sclerostin is independently positively associated with increased carotid intima-media thickness (CIMT) and with the risk of carotid plaque presence and aortic calcification.12 However, Gaudio et al. showed higher sclerostin and DKK-1 concentrations in postmenopausal women with T2DM than in healthy controls and a negative correlation with CIMT only in the T2DM group.11 Thus, sclerostin concentration was an independent predictor of CIMT in T2DM patients. In patients with T2DM, sclerostin was likely higher due to the presence of atherosclerotic lesions and the presence of cells derived from an osteogenic lineage inside the arterial wall, which may be the source of circulating sclerostin.136 Therefore, higher sclerostin levels in patients with CVD may reflect the advanced progression of atherosclerosis and plaque calcification.

Sclerostin and vascular calcification

Recently, it was shown that SOST knockout mice or the administration of anti-sclerostin antibodies resulted in enhanced bone formation and mineralization.137, 138 However, the data describing the role of sclerostin as an important risk factor for vascular calcification raise doubt.139 It has been found that induction of renal failure in SOST knockout mice resulted in the development of vascular calcification.140 However, while low levels of sclerostin increased bone formation,141, 142 this process did not prevent increased vascular mineralization.138 In addition, in DBA/2J mice that are more susceptible to the development of ectopic calcifications without renal failure,143 treatment with anti-sclerostin antibodies and a diet that included warfarin resulted in the development of aortic and renal arteries calcifications.138 Thus, these results suggest that sclerostin prevents vessel calcification in the aorta, kidney and cardiac arteries. This hypothesis seems to be supported by observations that expression of sclerostin mRNA and protein occurs in calcified vessels in both mice and humans,144 and plasma sclerostin levels are inversely associated with mortality among patients with CKD.145 It seems that locally produced sclerostin in the calcified tissues may act as a counter mechanism against further ectopic calcification. The mechanism may be similar to bones in that sclerostin binds to LRP5 receptors and inhibits the Wnt pathway in VSMCs. It seems that sclerostin may also act by indirect stimulation of FGF-23,146 resulting in urinary phosphate excretion, which lowers the plasma phosphate level.

Sclerostin and aneurysms

Under physiological conditions, VSMCs produce collagen and elastin, which are responsible for the strength and elasticity of arteries and the aorta. However, during atherosclerosis, the phenotype of VSMCs is modified, and they start producing matrix metalloproteinases (MMPs) that are involved in the degradation of the extracellular matrix, which in turn contributes to the development of aneurysms.112

A study by Kirshna et al. reported the downregulation of sclerostin and activation of the Wnt/β-catenin pathway in abdominal aortic aneurysms (AAA)23 in both mouse and human aortas. Upregulation of Wnt target genes was also detected in that arterial intima and media during the aging processes.147 The development of an aneurysm may stem from epigenetic changes in several genes, including excessive methylation of one of the CpG islands in the SOST promoter and subsequent inhibition of gene activity by up to 75%, as shown in human osteocytes.148, 149

Physiologically, collagen and elastin fibers maintain arterial width and elasticity. During the development of an aneurysm, fragmentation of collagen and elastin fibers occurs, resulting in decreased arterial wall strength.150 Results of studies performed on mouse fibroblasts indicate that by inhibiting the Wnt pathway, sclerostin enhances the expression of genes encoding extracellular matrix proteins responsible for maintaining the aorta structure.151

It is known that Wnt signaling controls the expression of OPG and OPN. Osteopontin activates proteolytic pathways and MMP-9 activity,81 and is engaged in the promotion of inflammation.80 In a mouse model, low OPN levels limited the development of AAA,152 and it is interesting to note that OPG promotes the MMP-2 and MMP-9 release and activity from monocytes and VSMCs,153, 154 leading to instability of the arterial wall. Furthermore, OPG concentration correlated positively with AAA progression148 and was positively associated with aortic diameter, MMP-2 and MMP-9 activity, cathepsin activity, and the number of lymphocytes inside the wall of aortic aneurysms, all being well-established parameters of AAA pathogenesis and severity.83, 85 Moreover, OPG deficiency protected against aortic angiotensin II-induced aneurysm development and rupture in mice.155

In a study performed in a mouse model, results showed that sclerostin overexpression or administration inhibited angiotensin II-induced aneurysm formation in the thoracic and abdominal aorta and the development of atherosclerosis.23 In line with this finding, inhibition of the Wnt pathway by sclerostin protected against the AAA development by downregulation of pro-aneurysmal genes in mice.23 Potentially, the inhibition of Wnt signaling may decrease the expression of OPN, OPG and MMP-9, and thus attenuate aortic wall inflammation and extracellular matrix degradation.23

Sclerostin and mortality

An investigation by Zeng et al. found a U-shaped association between sclerostin levels and vascular calcification and mortality.156 Even though atherosclerosis progresses with aging, it was shown that sclerostin concentrations did not predict the occurrence of cardiovascular events during a 15-year observational period in a population-based prospective study, whereas DKK-1 level was such a predictor.157 Moreover, some data has shown that DKK-1 is released mainly from endothelial cells79 and can activate platelets,158 causes endothelial cell apoptosis and enhances the expression of molecules including pentraxin-3 and plasminogen activator inhibitor type 1, which contributes to inflammation and inhibits fibrinolysis.159

The effects of inhibition of sclerostin in the vasculature

Locally enhanced sclerostin production can potentially inhibit vascular calcification at the site in the arterial wall, although at the same time may exert a negative effect on the bones by increasing bone resorption and inhibiting bone formation after being released into the circulation.120 Administration of the sclerostin inhibitor romosozumab, an anti-sclerostin antibody used to treat osteoporosis, resulted in a decrease in bone resorption and an increase in bone formation.160 The results of the ARCH study involving postmenopausal women with osteoporosis revealed a higher frequency of severe cardiovascular adverse events in the group treated with romosozumab than in patients treated with alendronate (2.5% compared to 1.9%).161 The most common cardiovascular events were myocardial infarctions and stroke. However, the results of another large study, FRAME, did not find an increase in cardiovascular risk between romosozumab and placebo groups.162 Several nonclinical studies have also been performed to elucidate the potential biological mechanisms mediating the increase in adverse cardiovascular events. It has been shown that romosozumab did not induce vasoconstriction in isolated human coronary artery cultures,163 and did not have any impact on cardiovascular or respiratory function in monkeys.164 Moreover, it did not initiate or exacerbate the process of arterial calcification in the absence of atherosclerosis in rats, even during lifetime exposure to this drug.165 In mouse models of atherosclerosis, administration of anti-sclerostin antibodies did not result in changes to plaque volume or mineralization, and histopathological examination of the aortas did not reveal increased hemorrhages, thrombosis or necrosis in a high-fat diet model of atherosclerosis due to treatment with romosozumab.163 Therapeutic anti-sclerostin antibodies did not increase the incidence of aneurysms23 and did not change biochemical parameters, platelet and endothelial activation or markers of inflammation in mouse models of the aortic aneurysm.23

Thus, the studies in animal models have not shown a significant effect of anti-sclerostin antibodies on the cardiovascular system. Furthermore, the data did not show evidence of the detrimental effects of sclerostin inhibition on the development of inflammation or exacerbation of atherosclerosis. The summary of findings concerning sclerostin levels in different clinical conditions is presented in Table 2.


Emerging data suggest there are similarities between bone homeostasis and vascular pathologies.166 Bone constitutes the buffering capacity for calcium and phosphorus, although the conditions of hypercalcemia and hyperphosphatemia result in stimulation of the arterial Wnt pathway. This Wnt pathway enhancement results in the initiation of transdifferentiation of VSMCs into a phenotype that secrets proteins, migrates, and induces mineralization and atherosclerosis. The Wnt pathway also stimulates the release and activity of other signaling regulators and growth factors, exacerbating RUNX2 expression and resulting in vascular calcification.


Sclerostin and DKK-1 detection in the calcified aorta in carotid plaques supports the hypothesis that upregulation of Wnt pathway inhibitors may be a defensive mechanism to restrain atherosclerosis. However, these methods have so far only been demonstrated under specific laboratory conditions and in animal models. It is also suggested that serum sclerostin concentrations mirror the advancement of arterial remodeling and vessel wall calcification, and it may represent the increased number of vascular cells transformed into osteogenic phenotypes. Indeed, higher serum sclerostin concentrations are observed in patients with atherosclerosis and vessel calcification when compared to healthy subjects. However, the value of serum sclerostin levels as a marker of advancement of global vascular calcification is lowered by the fact that they reflect 2 pools of sclerostin; one released by VSMCs due to their pathogenic transition to the osteogenic-like phenotype in arterial walls and a second that is derived physiologically from the bones.


Table 1. Mechanisms of sclerostin action


Genes mutation

Effects or results

In vitro human, mice osteoblast11, 109

sclerostin and Dickkopf family bind to LRP5/6 receptors and suppress osteogenesis

A human with atherosclerosis and heart valves calcifications21


sclerostin has been identified in vascular smooth muscle cells and aortic valves

A human with chronic kidney disease22

sclerostin is produced locally in calcified arteries

In vitro mice, cell osteoblasts culture incubated with TNF-α110

decreased sclerostin levels

Mice osteocytes culture incubated with glucocorticoids111

increased sclerostin levels

In vitro and ex vivo mice VSMC arterial cells with atherosclerosis and calcifications112

Enpp1−/− mouse

sclerostin expression identified in mature osteocyte – VSMC of aortic tissue

A human with sclerosteosis and VBD113

gene chromosome 17q12-q21 of sclerostin

loss of sclerostin function in bones

Mice limb bud114

SOST gain of function mutations

loss of Wnt pathway in limbs

A human with bone overgrowth115

LRP4 genes:

mutations – R1170W, W1186S

loss of function of LRP4 – sclerostin receptor in bone

Postmenopausal women treated with calcitriol116

enhanced serum sclerostin levels

VSMC – vascular smooth muscle cells; VDB – Van Buchem’s disease; TNF-α – tumor necrosis factor alpha.
Table 2. Association of sclerostin expression with cardiac and vascular pathologies




Human – postmenopausal type 2 diabetic women with atherosclerosis12


Serum sclerostin level positively correlates with plaque volume and vascular calcifications.

Humans over 65 years18


Serum sclerostin levels were higher in patients with PAD than in patients with normal ABI.

Human – Afro-Caribbean men19


Serum sclerostin levels positively correlate with coronary and aortic calcifications.

Human with atherosclerosis21

calcified and atherosclerotic aorta wall

Upregulated expression of sclerostin was detected in VSMCs.

Human with atherosclerosis21


Serum sclerostin level positively correlates with aortic calcification.

Human with atherosclerosis124

aorta wall, atherosclerotic plaques

Sclerostin expressions were detected in the heart, calcified aorta and atherosclerotic plaques.

Human with atherosclerosis130

atherosclerotic plaques and aortic calcifications

Sclerostin expressions were detected in aortic calcifications and plaques.

Higher levels of sclerostin in the media than in the intima.

VSMC – vascular smooth muscle cells; PAD – peripheral arterial disease; ABI – ankle-to-brachial index.


Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram
Fig. 2. Wnt signaling

References (166)

  1. Centers for Disease Control and Prevention (CDC). About Underlying Cause of Death, 1999–2020. Atlanta, USA: Centers for Disease Control and Prevention; 2018. Accessed September 2, 2016.
  2. Tsaousi A, Williams H, Lyon CA, et al. Wnt4/β-catenin signaling induces VSMC proliferation and is associated with intimal thickening. Circ Res. 2011;108(4):427–436. doi:10.1161/CIRCRESAHA.110.233999
  3. Arderiu G, Espinosa S, Peña E, Aledo R, Badimon L. Monocyte-secreted Wnt5a interacts with FZD5 in microvascular endothelial cells and induces angiogenesis through tissue factor signaling. J Mol Cell Biol. 2014;6(5):380–393. doi:10.1093/jmcb/mju036
  4. Du J, Li J. The role of Wnt signaling pathway in atherosclerosis and its relationship with angiogenesis. Exp Ther Med. 2018;16(3):1975–1981. doi:10.3892/etm.2018.6397
  5. Stegemann JP, Nerem RM. Altered response of vascular smooth muscle cells to exogenous biochemical stimulation in two- and three-dimensional culture. Exp Cell Res. 2003;283(2):146–155. doi:10.1016/S0014-4827(02)00041-1
  6. Tang X, Liu Y, Xiao Q, et al. Pathological cyclic strain promotes proliferation of vascular smooth muscle cells via the ACTH/ERK/STAT3 pathway. J Cell Biochem. 2018;119(10):8260–8270. doi:10.1002/jcb.26839
  7. Lin ME, Chen T, Leaf EM, Speer MY, Giachelli CM. Runx2 expression in smooth muscle cells is required for arterial medial calcification in mice. Am J Pathol. 2015;185(7):1958–1969. doi:10.1016/j.ajpath.2015.03.020
  8. Du J, Zu Y, Li J, et al. Extracellular matrix stiffness dictates Wnt expression through integrin pathway. Sci Rep. 2016;6:20395. doi:10.1038/srep20395
  9. Giachelli CM. Ectopic calcification: Gathering hard facts about soft tissue mineralization. Am J Pathol. 1999;154(3):671–675. doi:10.1016/S0002-9440(10)65313-8
  10. Sevetson B, Taylor S, Pan Y. Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST). J Biol Chem. 2004;279(14):13849–13858. doi:10.1074/jbc.M306249200
  11. Gaudio A, Privitera F, Pulvirenti I, Canzonieri E, Rapisarda R, Fiore CE. The relationship between inhibitors of the Wnt signalling pathway (sclerostin and Dickkopf-1) and carotid intima-media thickness in postmenopausal women with type 2 diabetes mellitus. Diab Vasc Dis Res. 2014;11(1):48–52. doi:10.1177/1479164113510923
  12. Morales-Santana S, García-Fontana B, García-Martín A, et al. Atherosclerotic disease in type 2 diabetes is associated with an increase in sclerostin levels. Diabetes Care. 2013;36(6):1667–1674. doi:10.2337/dc12-1691
  13. Chen A, Sun Y, Cui J, et al. Associations of sclerostin with carotid artery atherosclerosis and all-cause mortality in Chinese patients undergoing maintenance hemodialysis. BMC Nephrol. 2018;19(1):264. doi:10.1186/s12882-018-1046-7
  14. Scimeca M, Anemona L, Granaglia A, et al. Plaque calcification is driven by different mechanisms of mineralization associated with specific cardiovascular risk factors. Nutr Metab Cardiovasc Dis. 2019;29(12):1330–1336. doi:10.1016/j.numecd.2019.08.009
  15. Frysz M, Gergei I, Scharnagl H, et al. Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors. J Bone Miner Res. 2022;37(2):273–284. doi:10.1002/jbmr.4467
  16. Zhao B, Chen A, Wang H, et al. The relationship between sclerostin and carotid artery atherosclerosis in patients with stage 3–5 chronic kidney disease. Int Urol Nephrol. 2020;52(7):1329–1336. doi:10.1007/s11255-020-02495-x
  17. He XW, Wang E, Bao YY, et al. High serum levels of sclerostin and Dickkopf-1 are associated with acute ischaemic stroke. Atherosclerosis. 2016;253:22–28. doi:10.1016/j.atherosclerosis.2016.08.003
  18. Teng IC, Wang JH, Lee CJ, Hou JS, Hsu BG. Serum sclerostin as an independent marker of peripheral artery disease in elderly persons. Int J Clin Exp Pathol. 2018;11(5):2816–2821. PMID:31938401. PMCID:PMC6958239.
  19. Kuipers AL, Miljkovic I, Carr JJ, et al. Association of circulating sclerostin with vascular calcification in Afro-Caribbean men. Atherosclerosis. 2015;239(1):218–223. doi:10.1016/j.atherosclerosis.2015.01.010
  20. Morena M, Jaussent I, Dupuy AM, et al. Osteoprotegerin and sclerostin in chronic kidney disease prior to dialysis: Potential partners in vascular calcifications. Nephrol Dial Transplant. 2015;30(8):1345–1356. doi:10.1093/ndt/gfv081
  21. Koos R, Brandenburg V, Mahnken AH, et al. Sclerostin as a potential novel biomarker for aortic valve calcification: An in-vivo and ex-vivo study. J Heart Valve Dis. 2013;22(3):317–325. PMID:24151757.
  22. Brandenburg VM, Kramann R, Koos R, et al. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: A cross-sectional study. BMC Nephrol. 2013;14:219. doi:10.1186/1471-2369-14-219
  23. Krishna SM, Seto SW, Jose RJ, et al. Wnt signaling pathway inhibitor sclerostin inhibits angiotensin II-induced aortic aneurysm and atherosclerosis. Arterioscler Thromb Vasc Biol. 2017;37(3):553–566. doi:10.1161/ATVBAHA.116.308723
  24. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4(2):68–75. doi:10.4161/org.4.2.5851
  25. Endo M, Nishita M, Fujii M, Minami Y. Insight into the role of Wnt5a-induced signaling in normal and cancer cells. Int Rev Cell Mol Biol. 2015;314:117–148. doi:10.1016/bs.ircmb.2014.10.003
  26. Dejana E. The role of Wnt signaling in physiological and pathological angiogenesis. Circ Res. 2010;107(8):943–952. doi:10.1161/CIRCRESAHA.110.223750
  27. Kühl M, Sheldahl LC, Park M, Miller JR, Moon RT. The Wnt/Ca2+ pathway: A new vertebrate Wnt signaling pathway takes shape. Trends Genet. 2000;16(7):279–283. doi:10.1016/S0168-9525(00)02028-X
  28. Couffinhal T, Dufourcq P, Duplàa C. Beta-catenin nuclear activation: Common pathway between Wnt and growth factor signaling in vascular smooth muscle cell proliferation? Circ Res. 2006;99(12):1287–1289. doi:10.1161/01.RES.0000253139.82251.31
  29. Wang X, Xiao Y, Mou Y, Zhao Y, Blankesteijn WM, Hall JL. A role for the beta-catenin/T-cell factor signaling cascade in vascular remodeling. Circ Res. 2002;90(3):340–347. doi:10.1161/hh0302.104466
  30. Marinou K, Christodoulides C, Antoniades C, Koutsilieris M. Wnt signaling in cardiovascular physiology. Trends Endocrinol Metab. 2012;23(12):628–636. doi:10.1016/j.tem.2012.06.001
  31. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–480. doi:10.1016/j.cell.2006.10.018
  32. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. Adipogenesis and WNT signalling. Trends Endocrinol Metab. 2009;20(1):16–24. doi:10.1016/j.tem.2008.09.002
  33. Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005;115(5):1210–1220. doi:10.1172/JCI24140
  34. Mani A, Radhakrishnan J, Wang H, et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science. 2007;315(5816):1278–1282. doi:10.1126/science.1136370
  35. Corada M, Nyqvist D, Orsenigo F, et al. The Wnt/beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Dev Cell. 2010;18(6):938–949. doi:10.1016/j.devcel.2010.05.006
  36. Duarte A, Hirashima M, Benedito R, et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 2004;18(20):2474–2478. doi:10.1101/gad.1239004
  37. Wan M, Yang C, Li J, et al. Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev. 2008;22(21):2968–2979. doi:10.1101/gad.1702708
  38. Wan M, Li J, Herbst K, et al. LRP6 mediates cAMP generation by G protein-coupled receptors through regulating the membrane targeting of Gα(s). Sci Signal. 2011;4(164):ra15. doi:10.1126/scisignal.2001464
  39. Johnson BG, Ren S, Karaca G, et al. Connective tissue growth factor domain 4 amplifies fibrotic kidney disease through activation of LDL receptor-related protein 6. J Am Soc Nephrol. 2017;28(6):1769–1782. doi:10.1681/ASN.2016080826
  40. Nishita M, Yoo SK, Nomachi A, et al. Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J Cell Biol. 2006;175(4):555–562. doi:10.1083/jcb.200607127
  41. Sasai N, Nakazawa Y, Haraguchi T, Sasai Y. The neurotrophin-receptor-related protein NRH1 is essential for convergent extension movements. Nat Cell Biol. 2004;6(8):741–748. doi:10.1038/ncb1158
  42. Lu W, Yamamoto V, Ortega B, Baltimore D. Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell. 2004;119(1):97–108. doi:10.1016/j.cell.2004.09.019
  43. Lu X, Borchers AGM, Jolicoeur C, Rayburn H, Baker JC, Tessier-Lavigne M. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature. 2004;430(6995):93–98. doi:10.1038/nature02677
  44. Wallingford JB, Habas R. The developmental biology of Dishevelled: An enigmatic protein governing cell fate and cell polarity. Development. 2005;132(20):4421–4436. doi:10.1242/dev.02068
  45. Tanegashima K, Zhao H, Dawid IB. WGEF activates Rho in the Wnt–PCP pathway and controls convergent extension in Xenopus gastrulation. EMBO J. 2008;27(4):606–617. doi:10.1038/emboj.2008.9
  46. Marlow F, Topczewski J, Sepich D, Solnica-Krezel L. Zebrafish Rho kinase 2 acts downstream of Wnt11 to mediate cell polarity and effective convergence and extension movements. Curr Biol. 2002;12(11):876–884. doi:10.1016/S0960-9822(02)00864-3
  47. Weiser DC, Pyati UJ, Kimelman D. Gravin regulates mesodermal cell behavior changes required for axis elongation during zebrafish gastrulation. Genes Dev. 2007;21(12):1559–1571. doi:10.1101/gad.1535007
  48. Habas R, Dawid IB, He X. Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation. Genes Dev. 2003;17(2):295–309. doi:10.1101/gad.1022203
  49. Li L, Yuan H, Xie W, et al. Dishevelled proteins lead to two signaling pathways: Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells. J Biol Chem. 1999;274(1):129–134. doi:10.1074/jbc.274.1.129
  50. Keller R, Davidson LA, Shook DR. How we are shaped: The biomechanics of gastrulation. Differentiation. 2003;71(3):171–205. doi:10.1046/j.1432-0436.2003.710301.x
  51. Slusarski DC, Pelegri F. Calcium signaling in vertebrate embryonic patterning and morphogenesis. Dev Biol. 2007;307(1):1–13. doi:10.1016/j.ydbio.2007.04.043
  52. Slusarski DC, Corces VG, Moon RT. Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature. 1997;390(6658):410–413. doi:10.1038/37138
  53. Sheldahl LC, Slusarski DC, Pandur P, Miller JR, Kühl M, Moon RT. Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos. J Cell Biol. 2003;161(4):769–777. doi:10.1083/jcb.200211094
  54. Kühl M, Sheldahl LC, Malbon CC, Moon RT. Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. J Biol Chem. 2000;275(17):12701–12711. doi:10.1074/jbc.275.17.12701
  55. Miller JR, Hocking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways. Oncogene. 1999;18(55):7860–7872. doi:10.1038/sj.onc.1203245
  56. Axelrod JD, Miller JR, Shulman JM, Moon RT, Perrimon N. Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev. 1998;12(16):2610–2622. doi:10.1101/gad.12.16.2610
  57. Hoang BH, Thomas JT, Abdul-Karim FW, et al. Expression pattern of two Frizzled-related genes, Frzb-1 and Sfrp-1, during mouse embryogenesis suggests a role for modulating action of Wnt family members. Dev Dyn. 1998;212(3):364–372. doi:10.1002/(SICI)1097-0177(199807)212:3<364::AID-AJA4>3.0.CO;2-F
  58. Hsieh JC, Kodjabachian L, Rebbert ML, et al. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 1999;398(6726):431–436. doi:10.1038/18899
  59. Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280(20):19883–19887. doi:10.1074/jbc.M413274200
  60. Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 1998;391(6665):357–362. doi:10.1038/34848
  61. Rodda SJ, McMahon AP. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. 2006;133(16):3231–3244. doi:10.1242/dev.02480
  62. Glass DA, Bialek P, Ahn JD, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8(5):751–764. doi:10.1016/j.devcel.2005.02.017
  63. Kim JB, Leucht P, Lam K, et al. Bone regeneration is regulated by Wnt signaling. J Bone Miner Res. 2007;22(12):1913–1923. doi:10.1359/jbmr.070802
  64. Movérare-Skrtic S, Henning P, Liu X, et al. Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat Med. 2014;20(11):1279–1288. doi:10.1038/nm.3654
  65. Zhong Z, Zylstra-Diegel CR, Schumacher CA, et al. Wntless functions in mature osteoblasts to regulate bone mass. Proc Natl Acad Sci U S A. 2012;109(33):E2197–E2204. doi:10.1073/pnas.1120407109
  66. Okamoto M, Udagawa N, Uehara S, et al. Noncanonical Wnt5a enhances Wnt/β-catenin signaling during osteoblastogenesis. Sci Rep. 2014;4:4493. doi:10.1038/srep04493
  67. Yamane T, Kunisada T, Tsukamoto H, et al. Wnt signaling regulates hemopoiesis through stromal cells. J Immunol. 2001;167(2):765–772. doi:10.4049/jimmunol.167.2.765
  68. Kobayashi Y, Thirukonda GJ, Nakamura Y, et al. Wnt16 regulates osteoclast differentiation in conjunction with Wnt5a. Biochem Biophys Res Commun. 2015;463(4):1278–1283. doi:10.1016/j.bbrc.2015.06.102
  69. Yu B, Chang J, Liu Y, et al. Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-κB. Nat Med. 2014;20(9):1009–1017. doi:10.1038/nm.3586
  70. Maeda K, Kobayashi Y, Udagawa N, et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med. 2012;18(3):405–412. doi:10.1038/nm.2653
  71. Albanese I, Yu B, Al-Kindi H, et al. Role of noncanonical Wnt signaling pathway in human aortic valve calcification. Arterioscler Thromb Vasc Biol. 2017;37(3):543–552. doi:10.1161/ATVBAHA.116.308394
  72. Lee DK, Nathan Grantham R, Trachte AL, Mannion JD, Wilson CL. Activation of the canonical Wnt/β-catenin pathway enhances monocyte adhesion to endothelial cells. Biochem Biophys Res Commun. 2006;347(1):109–116. doi:10.1016/j.bbrc.2006.06.082
  73. Souilhol C, Serbanovic-Canic J, Fragiadaki M, et al. Endothelial responses to shear stress in atherosclerosis: A novel role for developmental genes. Nat Rev Cardiol. 2020;17(1):52–63. doi:10.1038/s41569-019-0239-5
  74. Quasnichka H, Slater SC, Beeching CA, Boehm M, Sala-Newby GB, George SJ. Regulation of smooth muscle cell proliferation by beta-catenin/T-cell factor signaling involves modulation of cyclin D1 and p21 expression. Circ Res. 2006;99(12):1329–1337. doi:10.1161/01.RES.0000253533.65446.33
  75. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317–325. doi:10.1038/nature10146
  76. Ezan J, Leroux L, Barandon L, et al. FrzA/sFRP-1, a secreted antagonist of the Wnt-Frizzled pathway, controls vascular cell proliferation in vitro and in vivo. Cardiovasc Res. 2004;63(4):731–738. doi:10.1016/j.cardiores.2004.05.006
  77. Kim J, Kim J, Kim DW, et al. Wnt5a induces endothelial inflammation via beta-catenin-independent signaling. J Immunol. 2010;185(2):1274–1282. doi:10.4049/jimmunol.1000181
  78. Yang D, Li S, Duan X, et al. TLR4 induced Wnt3a-Dvl3 restrains the intensity of inflammation and protects against endotoxin-driven organ failure through GSK3β/β-catenin signaling. Mol Immunol. 2020;118:153–164. doi:10.1016/j.molimm.2019.12.013
  79. Ueland T, Otterdal K, Lekva T, et al. Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29(8):1228–1234. doi:10.1161/ATVBAHA.109.189761
  80. Borrell-Pagès M, Romero JC, Juan-Babot O, Badimon L. Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages. Eur Heart J. 2011;32(22):2841–2850. doi:10.1093/eurheartj/ehr062
  81. Viñas JL, Sola A, Jung M, et al. Inhibitory action of Wnt target gene osteopontin on mitochondrial cytochrome c release determines renal ischemic resistance. Am J Physiol Renal Physiol. 2010;299(1):F234–F242. doi:10.1152/ajprenal.00687.2009
  82. Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest. 2001;107(9):1055–1061. doi:10.1172/JCI12980
  83. Lai CF, Seshadri V, Huang K, et al. An osteopontin-NADPH oxidase signaling cascade promotes pro-matrix metalloproteinase 9 activation in aortic mesenchymal cells. Circ Res. 2006;98(12):1479–1489. doi:10.1161/01.RES.0000227550.00426.60
  84. Li Y, Toraldo G, Li A, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839–3848. doi:10.1182/blood-2006-07-037994
  85. Koole D, Hurks R, Schoneveld A, et al. Osteoprotegerin is associated with aneurysm diameter and proteolysis in abdominal aortic aneurysm disease. Arterioscler Thromb Vasc Biol. 2012;32(6):1497–1504. doi:10.1161/ATVBAHA.111.243592
  86. Akhmetshina A, Palumbo K, Dees C, et al. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun. 2012;3:735. doi:10.1038/ncomms1734
  87. Königshoff M, Balsara N, Pfaff EM, et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 2008;3(5):e2142. doi:10.1371/journal.pone.0002142
  88. Colwell AS, Krummel TM, Longaker MT, Lorenz HP. Wnt-4 expression is increased in fibroblasts after TGF-beta1 stimulation and during fetal and postnatal wound repair. Plast Reconstr Surg. 2006;117(7):2297–2301. doi:10.1097/01.prs.0000218708.16909.31
  89. He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y. Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 2009;20(4):765–776. doi:10.1681/ASN.2008060566
  90. He W, Zhang L, Ni A, et al. Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proc Natl Acad Sci U S A. 2010;107(49):21110–21115. doi:10.1073/pnas.1004708107
  91. Trensz F, Haroun S, Cloutier A, Richter MV, Grenier G. A muscle resident cell population promotes fibrosis in hindlimb skeletal muscles of mdx mice through the Wnt canonical pathway. Am J Physiol Cell Physiol. 2010;299(5):C939–C947. doi:10.1152/ajpcell.00253.2010
  92. Semënov MV, Zhang X, He X. DKK1 antagonizes Wnt signaling without promotion of LRP6 internalization and degradation. J Biol Chem. 2008;283(31):21427–21432. doi:10.1074/jbc.M800014200
  93. Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol. 2004;15(12):2959–2964. doi:10.1097/01.ASN.0000145894.57533.C4
  94. Donoghue PS, Sun T, Gadegaard N, Riehle MO, Barnett SC. Development of a novel 3D culture system for screening features of a complex implantable device for CNS repair. Mol Pharm. 2014;11(7):2143–2150. doi:10.1021/mp400526n
  95. Patel JJ, Bourne LE, Davies BK, et al. Differing calcification processes in cultured vascular smooth muscle cells and osteoblasts. Exp Cell Res. 2019;380(1):100–113. doi:10.1016/j.yexcr.2019.04.020
  96. Persy V, D’Haese P. Vascular calcification and bone disease: The calcification paradox. Trends Mol Med. 2009;15(9):405–416. doi:10.1016/j.molmed.2009.07.001
  97. Campbell GR, Campbell JH. Smooth muscle phenotypic changes in arterial wall homeostasis: Implications for the pathogenesis of atherosclerosis. Exp Mol Pathol. 1985;42(2):139–162. doi:10.1016/0014-4800(85)90023-1
  98. Saidak Z, Le Henaff C, Azzi S, et al. Wnt/β-catenin signaling mediates osteoblast differentiation triggered by peptide-induced α5β1 integrin priming in mesenchymal skeletal cells. J Biol Chem. 2015;290(11):6903–6912. doi:10.1074/jbc.M114.621219
  99. Skalka N, Caspi M, Caspi E, Loh YP, Rosin-Arbesfeld R. Carboxypeptidase E: A negative regulator of the canonical Wnt signaling pathway. Oncogene. 2013;32(23):2836–2847. doi:10.1038/onc.2012.308
  100. Giachelli CM. The emerging role of phosphate in vascular calcification. Kidney Int. 2009;75(9):890–897. doi:10.1038/ki.2008.644
  101. Rahmani M, Read JT, Carthy JM, et al. Regulation of the versican promoter by the beta-catenin-T-cell factor complex in vascular smooth muscle cells. J Biol Chem. 2005;280(13):13019–13028. doi:10.1074/jbc.M411766200
  102. Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG. Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci. 2006;119(Pt 7):1283–1296. doi:10.1242/jcs.02883
  103. Cai T, Sun D, Duan Y, et al. WNT/β-catenin signaling promotes VSMCs to osteogenic transdifferentiation and calcification through directly modulating Runx2 gene expression. Exp Cell Res. 2016;345(2):206–217. doi:10.1016/j.yexcr.2016.06.007
  104. Wu X, Wang J, Jiang H, et al. Wnt3a activates β1-integrin and regulates migration and adhesion of vascular smooth muscle cells. Mol Med Rep. 2014;9(4):1159–1164. doi:10.3892/mmr.2014.1937
  105. Wang Z, Shu W, Lu MM, Morrisey EE. Wnt7b activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with Fzd1, Fzd10, and LRP5. Mol Cell Biol. 2005;25(12):5022–5030. doi:10.1128/MCB.25.12.5022-5030.2005
  106. Behrmann A, Zhong D, Sabaeifard P, Goodarzi M, Lemoff A, Towler D. Wnt16 regulates vascular matrix metabolism and arterial stiffness in the ldlr–/– mouse model of diet-induced metabolic syndrome Arterioscler Thromb Vasc Biol. 2020;40:A331. doi: 10.1161/CIRCRESAHA.119.316141.
  107. Durosier C, Van Lierop A, Ferrari S, Chevalley T, Papapoulos S, Rizzoli R. Association of circulating sclerostin with bone mineral mass, microstructure, and turnover biochemical markers in healthy elderly men and women. J Clin Endocrinol Metab. 2013;98(9):3873–3883. doi:10.1210/jc.2013-2113
  108. Caporilli S, Latinkic BV. Ventricular cell fate can be specified until the onset of myocardial differentiation. Mech Dev. 2016;139:31–41. doi:10.1016/j.mod.2016.01.001
  109. Li X, Liu P, Liu W, et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet. 2005;37(9):945–952. doi:10.1038/ng1614
  110. Vincent C, Findlay DM, Welldon KJ, et al. Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFalpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts. J Bone Miner Res. 2009;24(8):1434–1449. doi:10.1359/jbmr.090305
  111. Sato AY, Cregor M, Delgado-Calle J, et al. Protection from glucocorticoid-induced osteoporosis by anti-catabolic signalling in the absence of Sost/sclerostin. J Bone Miner Res. 2016;31(10):1791–1802. doi:10.1002/jbmr.2869
  112. Zhu D, Mackenzie NCW, Millán JL, Farquharson C, MacRae VE. The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS One. 2011;6(5):e19595. doi:10.1371/journal.pone.0019595
  113. Van Hul W, Balemans W, Van Hul E, et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet. 1998;62(2):391–399. doi:10.1086/301721
  114. Collette NM, Genetos DC, Murugesh D, Harland RM, Loots GG. Genetic evidence that SOST inhibits WNT signaling in the limb. Dev Biol. 2010;342(2):169–179. doi:10.1016/j.ydbio.2010.03.021
  115. Leupin O, Piters E, Halleux C, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286(22):19489–19500. doi:10.1074/jbc.M110.190330
  116. Cheng Q, Wu X, Du Y, et al. Levels of serum sclerostin, FGF-23, and intact parathyroid hormone in postmenopausal women treated with calcitriol. Clin Interv Aging. 2018;13:2367–2374. doi:10.2147/CIA.S186199
  117. Kubota T, Michigami T, Ozono K. Wnt signaling in bone. Clin Pediatr Endocrinol. 2010;19(3):49–56. doi:10.1297/cpe.19.49
  118. Evenepoel P, D’Haese P, Brandenburg V. Sclerostin and DKK1: New players in renal bone and vascular disease. Kidney Int. 2015;88(2):235–240. doi:10.1038/ki.2015.156
  119. Reddi AH. Initiation and promotion of endochondral bone formation by bone morphogenetic proteins: Potential implications for avian tibial dyschondroplasia. Poult Sci. 2000;79(7):978–981. doi:10.1093/ps/79.7.978
  120. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One. 2011;6(10):e25900. doi:10.1371/journal.pone.0025900
  121. Wang JS, Mazur CM, Wein MN. Sclerostin and osteocalcin: Candidate bone-produced hormones. Front Endocrinol. 2021;12:584147. doi:10.3389/fendo.2021.584147
  122. Cianferotti L, Demay MB. VDR-mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells. J Cell Biochem. 2007;101(1):80–88. doi:10.1002/jcb.21151
  123. Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone. 2005;37(2):148–158. doi:10.1016/j.bone.2005.03.018
  124. Didangelos A, Yin X, Mandal K, Baumert M, Jahangiri M, Mayr M. Proteomics characterization of extracellular space components in the human aorta. Mol Cell Proteomics. 2010;9(9):2048–2062. doi:10.1074/mcp.M110.001693
  125. Hampson G, Edwards S, Conroy S, Blake GM, Fogelman I, Frost ML. The relationship between inhibitors of the Wnt signalling pathway (Dickkopf-1(DKK1) and sclerostin), bone mineral density, vascular calcification and arterial stiffness in post-menopausal women. Bone. 2013;56(1):42–47. doi:10.1016/j.bone.2013.05.010
  126. Sage AP, Tintut Y, Demer LL. Regulatory mechanisms in vascular calcification. Nat Rev Cardiol. 2010;7(9):528–536. doi:10.1038/nrcardio.2010.115
  127. Shao JS, Cai J, Towler DA. Molecular mechanisms of vascular calcification: Lessons learned from the aorta. Arterioscler Thromb Vasc Biol. 2006;26(7):1423–1430. doi:10.1161/01.ATV.0000220441.42041.20
  128. Wu J, Ma L, Wu L, Jin Q. Wnt-β-catenin signaling pathway inhibition by sclerostin may protect against degradation in healthy but not osteoarthritic cartilage. Mol Med Rep. 2017;15(5):2423–2432. doi:10.3892/mmr.2017.6278
  129. Pikilidou M, Yavropoulou M, Antoniou M, Yovos J. The contribution of osteoprogenitor cells to arterial stiffness and hypertension. J Vasc Res. 2015;52(1):32–40. doi:10.1159/000381098
  130. Leto G, D’Onofrio L, Lucantoni F, et al. Sclerostin is expressed in the atherosclerotic plaques of patients undergoing carotid endarterectomy. Diabetes Metab Res Rev. 2019;35(1):e3069. doi:10.1002/dmrr.3069
  131. Li M, Zhou H, Yang M, Xing C. Relationship between serum sclerostin, vascular sclerostin expression and vascular calcification assessed by different methods in ESRD patients eligible for renal transplantation: A cross-sectional study. Int Urol Nephrol. 2019;51(2):311–323. doi:10.1007/s11255-018-2033-4
  132. Register TC, Hruska KA, Divers J, et al. Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-Diabetes Heart Study. J Clin Endocrinol Metab. 2014;99(1):315–321. doi:10.1210/jc.2013-3168
  133. Claes KJ, Viaene L, Heye S, Meijers B, d’Haese P, Evenepoel P. Sclerostin: Another vascular calcification inhibitor? J Clin Endocrinol Metab. 2013;98(8):3221–3228. doi:10.1210/jc.2013-1521
  134. Thambiah S, Roplekar R, Manghat P, et al. Circulating sclerostin and Dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): Relationship with bone density and arterial stiffness. Calcif Tissue Int. 2012;90(6):473–480. doi:10.1007/s00223-012-9595-4
  135. Catalano A, Pintaudi B, Morabito N, et al. Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus. Eur J Endocrinol. 2014;171(3):293–300. doi:10.1530/EJE-14-0106
  136. García-Martín A, Rozas-Moreno P, Reyes-García R, et al. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97(1):234–241. doi:10.1210/jc.2011-2186
  137. Poole KES, Van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005;19(13):1842–1844. doi:10.1096/fj.05-4221fje
  138. De Maré A, Opdebeeck B, Neven E, D’Haese PC, Verhulst A. Sclerostin protects against vascular calcification development in mice. J Bone Miner Res. 2022;37(4):687–699. doi:10.1002/jbmr.4503
  139. McClung M, Grauer A. Romosozumab in postmenopausal women with osteopenia. N Engl J Med. 2014;370(17):1664–1665. doi:10.1056/NEJMc1402396
  140. Van Lierop AH, Moester MJC, Hamdy NAT, Papapoulos SE. Serum Dickkopf 1 levels in sclerostin deficiency. J Clin Endocrinol Metab. 2014;99(2):E252–E256. doi:10.1210/jc.2013-3278
  141. Li X, Ominsky MS, Niu QT, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23(6):860–869. doi:10.1359/jbmr.080216
  142. Kaesler N, Verhulst A, De Maré A, et al. Sclerostin deficiency modifies the development of CKD-MBD in mice. Bone. 2018;107:115–123. doi:10.1016/j.bone.2017.11.015
  143. Krüger T, Oelenberg S, Kaesler N, et al. Warfarin induces cardiovascular damage in mice. Arterioscler Thromb Vasc Biol. 2013;33(11):2618–2624. doi:10.1161/ATVBAHA.113.302244
  144. De Maré A, Maudsley S, Azmi A, et al. Sclerostin as regulatory molecule in vascular media calcification and the bone–vascular axis. Toxins (Basel). 2019;11(7):428. doi:10.3390/toxins11070428
  145. Lips L, De Roij Van Zuijdewijn CLM, Ter Wee PM, et al. Serum sclerostin: Relation with mortality and impact of hemodiafiltration. Nephrol Dial Transplant. 2017;32(7):1217–1223. doi:10.1093/ndt/gfw246
  146. Ryan ZC, Ketha H, McNulty MS, et al. Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium. Proc Natl Acad Sci U S A. 2013;110(15):6199–6204. doi:10.1073/pnas.1221255110
  147. Marchand A, Atassi F, Gaaya A, et al. The Wnt/beta-catenin pathway is activated during advanced arterial aging in humans. Aging Cell. 2011;10(2):220–232. doi:10.1111/j.1474-9726.2010.00661.x
  148. Moran CS, Clancy P, Biros E, et al. Association of PPARgamma allelic variation, osteoprotegerin and abdominal aortic aneurysm. Clin Endocrinol (Oxf). 2010;72(1):128–132. doi:10.1111/j.1365-2265.2009.03615.x
  149. Delgado-Calle J, Sañudo C, Bolado A, et al. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J Bone Miner Res. 2012;27(4):926–937. doi:10.1002/jbmr.1491
  150. Isenburg JC, Simionescu DT, Starcher BC, Vyavahare NR. Elastin stabilization for treatment of abdominal aortic aneurysms. Circulation. 2007;115(13):1729–1737. doi:10.1161/CIRCULATIONAHA.106.672873
  151. Hamburg-Shields E, DiNuoscio GJ, Mullin NK, Lafyatis R, Atit RP. Sustained β-catenin activity in dermal fibroblasts promotes fibrosis by upregulating expression of extracellular matrix protein-coding genes. J Pathol. 2015;235(5):686–697. doi:10.1002/path.4481
  152. Bruemmer D, Collins AR, Noh G, et al. Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. J Clin Invest. 2003;112(9):1318–1331. doi:10.1172/JCI200318141
  153. Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J. Association of osteoprotegerin with human abdominal aortic aneurysm progression. Circulation. 2005;111(23):3119–3125. doi:10.1161/CIRCULATIONAHA.104.464727
  154. Bennett BJ, Scatena M, Kirk EA, et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice. Arterioscler Thromb Vasc Biol. 2006;26(9):2117–2124. doi:10.1161/01.ATV.0000236428.91125.e6
  155. Moran CS, Jose RJ, Biros E, Golledge J. Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture in the apolipoprotein E-knockout mouse. Arterioscler Thromb Vasc Biol. 2014;34(12):2609–2616. doi:10.1161/ATVBAHA.114.304587
  156. Zeng C, Guo C, Cai J, Tang C, Dong Z. Serum sclerostin in vascular calcification and clinical outcome in chronic kidney disease. Diab Vasc Dis Res. 2018;15(2):99–105. doi:10.1177/1479164117742316
  157. Klingenschmid G, Tschiderer L, Himmler G, et al. Associations of serum Dickkopf-1 and sclerostin with cardiovascular events: Results from the prospective Bruneck study. J Am Heart Assoc. 2020;9(6):e014816. doi:10.1161/JAHA.119.014816
  158. Di M, Wang L, Li M, et al. Dickkopf1 destabilizes atherosclerotic plaques and promotes plaque formation by inducing apoptosis of endothelial cells through activation of ER stress. Cell Death Dis. 2017;8(7):e2917. doi:10.1038/cddis.2017.277
  159. Pontremoli M, Brioschi M, Baetta R, Ghilardi S, Banfi C. Identification of DKK-1 as a novel mediator of statin effects in human endothelial cells. Sci Rep. 2018;8(1):16671. doi:10.1038/s41598-018-35119-7
  160. Chavassieux P, Chapurlat R, Portero‐Muzy N, et al. Bone-forming and antiresorptive effects of romosozumab in postmenopausal women with osteoporosis: Bone histomorphometry and microcomputed tomography analysis after 2 and 12 months of treatment. J Bone Miner Res. 2019;34(9):1597–1608. doi:10.1002/jbmr.3735
  161. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417–1427. doi:10.1056/NEJMoa1708322
  162. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532–1543. doi:10.1056/NEJMoa1607948
  163. Turk JR, Deaton AM, Yin J, et al. Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin, for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Regul Toxicol Pharmacol. 2020;115:104697. doi:10.1016/j.yrtph.2020.104697
  164. Ominsky MS, Boyd SK, Varela A, et al. Romosozumab improves bone mass and strength while maintaining bone quality in variectomized cynomolgus monkeys. J Bone Miner Res. 2017;32(4):788–801. doi:10.1002/jbmr.3036
  165. Chouinard L, Felx M, Mellal N, et al. Carcinogenicity risk assessment of romosozumab: A review of scientific weight-of-evidence and findings in a rat lifetime pharmacology study. Regul Toxicol Pharmacol. 2016;81:212–222. doi:10.1016/j.yrtph.2016.08.010
  166. Towler DA. Commonalities between vasculature and bone: An osseocentric view of arteriosclerosis. Circulation. 2017;135(4):320–322. doi:10.1161/CIRCULATIONAHA.116.022562