Canonical Wnt Signaling in Differentiated Osteoblasts Controls Osteoclast Differentiation

Glass, Donald A.; Bialek, Peter; Ahn, Jae S.; Starbuck, Michael W.; Patel, Millan S.; Clevers, Hans; Taketo, M.; Long, Fanxin; McMahon, Andrew P.; Lang, Richard A.; Karsenty, Gérard

doi:10.1016/j.devcel.2005.02.017

Cited by 1,415 publications

(1,175 citation statements)

References 33 publications

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“…DKK-1 and SOST are soluble inhibitors of canonical WNT signaling (34), which plays an important role in bone development by inhibiting OC differentiation (35), stimulating osteoblastogenesis and mineralizing activity of osteoblasts (36). We detected DKK-1 expression in primary tumor, according to previously published data reporting its expression in some human specimens of tumors, and suggesting that a cancermediated modulation of WNT activity affects the metastatic phenotype (37)(38)(39).…”

Section: Discussionsupporting

confidence: 72%

Bone metastases in gastric cancer follow a RANKL-independent mechanism

et al. 2013

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Abstract. Gastric cancer is one of the most common and lethal malignancies worldwide. Bone metastases in gastric cancer are less common than in other solid tumors, but when they occur the prognosis is generally poor. Increased osteoclastogenesis and osteoclast activity are common features in bone metastases caused by different osteotropic cancer. We investigated osteoclastogenesis and its mechanisms in gastric cancer by enrolling 31 newly diagnosed gastric cancer patients and 45 healthy controls. We studied in vitro osteoclastogenesis in the peripheral blood mononuclear cell cultures of patients and controls, showing spontaneous osteoclastogenesis for half of the patients. This osteoclastogenesis was RANKL-and TNF-α-independent. We analyzed primary tumor and bone metastatic tissues of gastric cancer for the expression of genes involved in osteoclastogenesis. The expression of transforming growth factor-β (TGF-β), osteoprotegerin (OPG), IL-7 and dickkopf-1 (DKK-1) was higher in primary tumors than in bone metastases. RANKL was not detectable in primary tumor or in bone metastatic tissue. The serum RANKL level was significantly higher in healthy controls than in patients, and it was not related to osteoclastogenesis, thereby suggesting that RANKL is not involved in the bone metastatic mechanisms in gastric cancer. We hypothesized a role of RANKL in angiogenesis, thus we compared the serum levels of RANKL to those of VEGF, since VEGF is directly related to angiogenesis. Different from RANKL, the VEGF serum levels were higher in gastric patients than in controls, suggesting a block of the angiogenesis inhibition due to RANKL. RANKL and VEGF serum levels were not predictive of overall survival in our cohort of gastric patients.

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Section: Discussionsupporting

confidence: 72%

Bone metastases in gastric cancer follow a RANKL-independent mechanism

et al. 2013

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“…Increased cyclin D1 is associated with bone anabolism and anti-apoptosis (36,(47)(48)(49) ; and increased OPG is responsible for inhibition of osteoclast formation and resorption. (27,28,50) Thus, whereas glucocorticoids oppose all Wnt/b-catenin signaling in the presence of Sost/sclerostin, the hormones only oppose signaling associated with bone formation/survival in the absence of Sost/sclerostin.…”

Section: Resultsmentioning

confidence: 99%

“…(24)(25)(26) In addition, genetic manipulation of b-catenin, the mediator of the canonical Wnt pathway, affects bone resorption due to regulation of the expression of osteoprotegerin (OPG), the decoy receptor for receptor activator of nuclear factor kappa B ligand (RANKL), demonstrating that this pathway is also linked to resorption. (27,28) Therefore, the Wnt/b-catenin signaling cascade can regulate bone mass by both bone anabolic and anticatabolic mechanisms. Further, activation of Wnt/b-catenin signaling promotes osteoblast and osteocyte survival.…”

Section: Introductionmentioning

confidence: 99%

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Sato

Cregor

Delgado‐Calle

et al. 2016

Journal of Bone and Mineral Research

109

108

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Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/b-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/b-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost -/-mice. The high bone mass exhibited by Sost -/-mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost -/-mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/b-catenin pathway by decreasing the expression of genes associated with both anticatabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost -/-mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/b-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/b-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/b-catenin signaling.

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“…Bones were fixed and embedded in methyl methacrylate resin. (21) Osteoclast surface was determined by using tartrate-resistant acid phosphatase (TRAP)-stained paraffin sections of metatarsal in 2-week-old mice. All parameters were quantified with the Osteomeasure system (Osteometrics, Atlanta, GA, USA) according to standard procedures.…”

Section: Analysis Of Bone Histomorphometrymentioning

confidence: 99%

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Oh¹,

Ryu²,

Jeon³

et al. 2012

Journal of Bone and Mineral Research

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Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte-and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption. ß

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Canonical Wnt Signaling in Differentiated Osteoblasts Controls Osteoclast Differentiation

Cited by 1,415 publications

References 33 publications

Bone metastases in gastric cancer follow a RANKL-independent mechanism

Bone metastases in gastric cancer follow a RANKL-independent mechanism

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

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