Sclerostin and Dickkopf-1 as Therapeutic Targets in Bone Diseases

Ke, Hua Zhu; Richards, William G.; Li, Xiaodong; Ominsky, Michael S.

doi:10.1210/er.2011-1060

Cited by 376 publications

(306 citation statements)

References 225 publications

(237 reference statements)

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“…These findings strongly suggest that osteocytes also might mediate anabolism induced by systemic activation of the pathway, with inhibitors of GSK3β or neutralizing antibodies of sclerostin, or even in human mutations of components of the Wnt pathway (4). The fact that osteocytes comprise most of the cells in bone might explain why bone anabolism is the most patent outcome of systemic Wnt activation, even when inhibition of resorption might be also manifested in some instances (36).…”

Section: Discussionmentioning

confidence: 99%

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Tu¹,

Delgado‐Calle

Condon³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

245

237

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Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcat Ot mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat Ot mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat Ot mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat Ot mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.osteocytes | canonical Wnt | beta-catenin | bone anabolism | notch signaling

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Section: Discussionmentioning

confidence: 99%

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Tu¹,

Delgado‐Calle

Condon³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

245

237

View full text Add to dashboard Cite

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“…Future studies are required to investigate the roles of Wnt/β-catenin, as well as numerous other signaling pathways, in the occlusal hypofunction status and their underlying mechanisms. Sclerostin is emerging as a promising therapeutic target in bone disease therapy (43). Various animal studies demonstrated that the sclerostin antibody was effective in preventing unloading-induced osteoporosis (44,45).…”

Section: B a C Dmentioning

confidence: 99%

Sclerostin is essential for alveolar bone loss in occlusal hypofunction

Wang

Sun

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Bone loss is caused by occlusal hypofunction and is a serious health concern. This is particularly true of tooth loss, which is common in the elderly. However, the cellular and molecular mechanisms underlying bone loss have yet to be fully elucidated. Sclerostin and Wnt/β-catenin signaling have previously been reported to serve important roles in regulating bone remodeling. Therefore, the present study aimed to investigate the involvement of sclerostin and Wnt/β-catenin signaling in occlusal hypofunction-induced alveolar bone remodeling. The unilateral maxillary molars of 14 male Sprague-Dawley rats were extracted in order to establish a model of occlusal hypofunction. For each rat, the non-extraction side was treated as the control group for comparisons with the extraction side. At 8 weeks after tooth extraction, the rats were sacrificed and alveolar bone specimens were harvested for X-ray radiography, micro-computed tomography (CT) and histological and immunohistochemical examinations. Bone loss and architecture deterioration were observed at the occlusal hypofunction side. The bone mineral density was markedly decreased and the ratio of bone volume to total volume was significantly decreased at the hypofunction side, as compared with the control side (P<0.001). In addition, the number of osteoclasts at the hypofunction side were significantly increased compared with that in the control side (P<0.001), as demonstrated using tartrate-resistant acid phosphatase staining. Furthermore, the protein expression levels of sclerostin and receptor activator of nuclear factor-κB ligand were increased, whereas those of β-catenin were decreased, at the hypofunction side when compared with the control side. In conclusion, the results of the present study suggested that occlusal hypofunction-induced bone loss may be associated with upregulated expression of sclerostin, which, in turn, may inhibit the activity of the Wnt/β-catenin signaling pathway. IntroductionTooth loss is a common and serious health concern, particularly in the elderly. Although the incidence of tooth loss has declined in industrialized countries, the goal established by the World Health Organization of retaining 20 teeth at the age of 80 years has not been widely achieved (1,2). Mechanical stress has a crucial role in bone remodeling (3,4) and bone loss may occur as a result of reduced mechanical force, which is defined as disuse osteoporosis (5). Occlusal hypofunction due to tooth loss has a negative impact on jaw bone homeostasis (6). Tooth loss may lead to a reduced bite force in the antagonistic tooth and underlying alveolar bone during chewing. A lack of functional occlusion may induce active alveolar bone loss, including decreasing bone mass and volume (7,8). In addition, in certain pathological conditions, such as estrogen deficiency, functional occlusion has been revealed to slow down the rate of bone loss (9), whereas occlusal hypofunction was reported to accelerate bone loss (10,11). However, the cellular and molecular mechanisms under...

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“…The anti-SOST antibody (Scl-Ab) has shown very promising results in both human and animal models of low bone mass disorders and fracture healing. To avoid redundancy and to give full attention to the exciting results from Scl-Ab studies, we encourage you to read the recently published and highly thorough review by Ke et al (253).…”

Section: Sclerostinmentioning

confidence: 99%

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

2013

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The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone. Keywords: Wnt signaling; mouse models; Lrp5/Lrp6; β-catenin; skeletal phenotypes Bone Research (2013) 1: 27-71. doi: 10.4248/BR201301004 Overview of Wnt signal transductionWnts are a family of 19 mammalian proteins characterized by a conserved pattern of cysteine residues( 1). Wnts can activate several signaling pathways after binding to their cognate receptors, however, the bulk of this review will focus on the best characterized of these pathways, the so-called canonical pathway (Figure 1). This pathway results in the stabilization of the β-catenin protein and subsequent transactivation of target genes (2). It is initiated by Wnt ligands binding to a receptor complex that includes a member of the Frizzled (Fzd) family of seven-transmembrane receptors and either Lrp5, or the related Lrp6 protein(3). Engagement of this complex results in the phosphorylation of the cytoplasmic domain of Lrp5 or Lrp6, creating a binding site for the Axin protein.In the absence of an upstreamsignal, Axin exists in a multiprotein complex that also includes Adenomatous polyposis coli (APC) and the serine/ threonine protein kinase, Glycogen synthase kinase 3 α/β. This complex facilitates β-catenin for GSK3-dependent phosphorylation, targeting it for ubiquitin-depen- 28 dent proteolysis. Binding of Axin to phosphoryl...

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Sclerostin and Dickkopf-1 as Therapeutic Targets in Bone Diseases

Cited by 376 publications

References 225 publications

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Sclerostin is essential for alveolar bone loss in occlusal hypofunction

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

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