scholarly journals An Akt-dependent Increase in Canonical Wnt Signaling and a Decrease in Sclerostin Protein Levels Are Involved in Strontium Ranelate-induced Osteogenic Effects in Human Osteoblasts

2011 ◽  
Vol 286 (27) ◽  
pp. 23771-23779 ◽  
Author(s):  
Mark S. Rybchyn ◽  
Michael Slater ◽  
Arthur D. Conigrave ◽  
Rebecca S. Mason
Keyword(s):  
Bone Formation ◽  
Wnt Signaling ◽  
Strontium Ranelate ◽  
Nuclear Translocation ◽  
Negative Regulator ◽  
Bone Homeostasis ◽  
Canonical Wnt Signaling ◽  
Human Osteoblasts ◽  
Protein Levels ◽  
Canonical Wnt

Sclerostin is an important regulator of bone homeostasis and canonical Wnt signaling is a key regulator of osteogenesis. Strontium ranelate is a treatment for osteoporosis that has been shown to reduce fracture risk, in part, by increasing bone formation. Here we show that exposure of human osteoblasts in primary culture to strontium increased mineralization and decreased the expression of sclerostin, an osteocyte-specific secreted protein that acts as a negative regulator of bone formation by inhibiting canonical Wnt signaling. Strontium also activated, in an apparently separate process, an Akt-dependent signaling cascade via the calcium-sensing receptor that promoted the nuclear translocation of β-catenin. We propose that two discrete pathways linked to canonical Wnt signaling contribute to strontium-induced osteogenic effects in osteoblasts.

scholarly journals The Wnt Signaling Antagonist Kremen1 is Required for Development of Thymic Architecture

2006 ◽  
Vol 13 (2-4) ◽  
pp. 299-319 ◽  
Author(s):  
Masako Osada ◽  
Emi Ito ◽  
Hector A. Fermin ◽  
Edwin Vazquez-Cintron ◽  
Tadmiri Venkatesh ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Wnt Signaling Pathway ◽  
Fold Increase ◽  
Negative Regulator ◽  
Thymic Epithelial Cells ◽  
Canonical Wnt Signaling ◽  
Thymocyte Proliferation ◽  
Elevated Expression ◽  
Wnt Inhibitor ◽  
Canonical Wnt

Wnt signaling has been reported to regulate thymocyte proliferation and selection at several stages during T cell ontogeny, as well as the expression ofFoxN1in thymic epithelial cells (TECs). Kremen1 (Krm1) is a negative regulator of the canonical Wnt signaling pathway, and functions together with the secreted Wnt inhibitor Dickkopf (Dkk) by competing for the lipoprotein receptor-related protein (LRP)-6 co-receptor for Wnts. Herekrm1knockout mice were used to examinekrm1expression in the thymus and its function in thymocyte and TEC development.krm1expression was detected in both cortical and medullary TEC subsets, as well as in immature thymocyte subsets, beginning at the CD25+CD44+ (DN2) stage and continuing until the CD4+CD8+(DP) stage. Neonatal mice show elevated expression ofkrm1in all TEC subsets.krm1− / −mice exhibit a severe defect in thymic cortical architecture, including large epithelial free regions. Much of the epithelial component remains at an immature Keratin 5+(K5) Keratin 8+(K8) stage, with a loss of defined cortical and medullary regions. A TOPFlash assay revealed a 2-fold increase in canonical Wnt signaling in TEC lines derived fromkrm1− / −mice, when compared withkrm1+ / +derived TEC lines. Fluorescence activated cell sorting (FACS) analysis of dissociated thymus revealed a reduced frequency of both cortical (BP1+EpCAM+) and medullary (UEA-1+EpCAMhi) epithelial subsets, within thekrm1− / −thymus. Surprisingly, no change in thymus size, total thymocyte number or the frequency of thymocyte subsets was detected inkrm1− / −mice. However, our data suggest that a loss of Krm1 leads to a severe defect in thymic architecture. Taken together, this study revealed a new role for Krm1 in proper development of thymic epithelium.

scholarly journals Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin

2013 ◽  
Vol 200 (4) ◽  
pp. 537-549 ◽  
Author(s):  
Joachim Albers ◽  
Johannes Keller ◽  
Anke Baranowsky ◽  
Frank Timo Beil ◽  
Philip Catala-Lehnen ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Wnt Signaling ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Negative Influence ◽  
Canonical Wnt Signaling ◽  
Mouse Tissues ◽  
Canonical Wnt

Although Wnt signaling is considered a key regulatory pathway for bone formation, inactivation of β-catenin in osteoblasts does not affect their activity but rather causes increased osteoclastogenesis due to insufficient production of osteoprotegerin (Opg). By monitoring the expression pattern of all known genes encoding Wnt receptors in mouse tissues and bone cells we identified Frizzled 8 (Fzd8) as a candidate regulator of bone remodeling. Fzd8-deficient mice displayed osteopenia with normal bone formation and increased osteoclastogenesis, but this phenotype was not associated with impaired Wnt signaling or Opg production by osteoblasts. The deduced direct negative influence of canonical Wnt signaling on osteoclastogenesis was confirmed in vitro and through the generation of mice lacking β-catenin in the osteoclast lineage. Here, we observed increased bone resorption despite normal Opg production and a resistance to the anti-osteoclastogenic effect of Wnt3a. These results demonstrate that Fzd8 and β-catenin negatively regulate osteoclast differentiation independent of osteoblasts and that canonical Wnt signaling controls bone resorption by two different mechanisms.

scholarly journals A divergent canonical WNT-signaling pathway regulates microtubule dynamics

2004 ◽  
Vol 164 (2) ◽  
pp. 243-253 ◽  
Author(s):  
Lorenza Ciani ◽  
Olga Krylova ◽  
Matthew J. Smalley ◽  
Trevor C. Dale ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Canonical Wnt Signaling ◽  
Microtubule Stability ◽  
Gsk 3Β ◽  
Canonical Wnt

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β). In the canonical WNT pathway, the negative regulator Axin forms a complex with β-catenin and GSK-3β, resulting in β-catenin degradation. Inhibition of GSK-3β by DVL increases β-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3β through a transcription- and β-catenin–independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3β–mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3β, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.

scholarly journals R-spondin 3 deletion favors Erk phosphorylation to enhance Wnt signaling and bone formation

2021 ◽  
Author(s):  
Kenichi Nagano ◽  
Kei Yamana ◽  
Hiroaki Saito ◽  
Riku Kiviranta ◽  
Ana Clara Pedroni ◽  
...  
Keyword(s):  
Bone Density ◽  
Bone Formation ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Erk Signaling ◽  
Canonical Wnt Signaling ◽  
Erk Phosphorylation ◽  
High Bone ◽  
Canonical Wnt

Abstract Activation of Wnt signaling leads to high bone density. The R-spondin family of four secreted glycoproteins (Rspo1-4) amplifies Wnt signaling. In humans, RSPO3 variants are strongly associated with bone density, but how RSPO3 affects skeletal homeostasis is not fully understood. Here we show that in mice Rspo3 haplo-insufficiency or its targeted deletion in osteoprogenitors lead to an increase in bone formation and bone mass. Contrary to expectations, Rspo3 haplo-insufficiency results in canonical Wnt signaling activation. Using mouse embryonic fibroblasts we show that Rspo3 deficiency leads to activation of Erk signaling, stabilizing β-catenin. Furthermore, Rspo3 haplo-insufficiency impairs Dkk1 efficacy in blocking canonical Wnt signaling and prevents the in vivo inhibition of bone formation and bone mass induced by osteoblast-targeted expression of Dkk1. We conclude that Rspo3 haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling and impairing Dkk1’s inhibitory activity, which in turn lead to increased bone formation and bone mass.

scholarly journals Carboxypeptidase E: a negative regulator of the canonical Wnt signaling pathway

Oncogene ◽  
2012 ◽  
Vol 32 (23) ◽  
pp. 2836-2847 ◽  
Author(s):  
N Skalka ◽  
M Caspi ◽  
E Caspi ◽  
Y P Loh ◽  
R Rosin-Arbesfeld
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Canonical Wnt Signaling ◽  
Carboxypeptidase E ◽  
Canonical Wnt

scholarly journals Effect of Pulsed Electromagnetic Field on Bone Formation and Lipid Metabolism of Glucocorticoid-Induced Osteoporosis Rats through Canonical Wnt Signaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yuan Jiang ◽  
Hui Gou ◽  
Sanrong Wang ◽  
Jiang Zhu ◽  
Si Tian ◽  
...  
Keyword(s):  
Electromagnetic Field ◽  
Lipid Metabolism ◽  
Bone Formation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Pulsed Electromagnetic Field ◽  
Canonical Wnt Signaling ◽  
Pulsed Electromagnetic ◽  
Canonical Wnt

Pulsed electromagnetic field (PEMF) has been suggested as a promising method alternative to drug-based therapies for treating osteoporosis (OP), but the role of PEMF in GIOP animal models still remains unknown. This study was performed to investigate the effect of PEMF on bone formation and lipid metabolism and further explored the several important components and targets of canonical Wnt signaling pathway in GIOP rats. After 12 weeks of intervention, bone mineral density (BMD) level of the whole body increased significantly, serum lipid levels decreased significantly, and trabeculae were thicker in GIOP rats of PEMF group. PEMF stimulation upregulated the mRNA and protein expression of Wnt10b, LRP5,β-catenin, OPG, and Runx2 and downregulated Axin2, PPAR-γ, C/EBPα, FABP4, and Dkk-1. The results of this study suggested that PEMF stimulation can prevent bone loss and improve lipid metabolism disorders in GIOP rats. Canonical Wnt signaling pathway plays an important role in bone formation and lipid metabolism during PEMF stimulation.

scholarly journals R-spondin 3 deletion favors Erk phosphorylation to enhance Wnt signaling and bone formation

2021 ◽  
Author(s):  
Kenichi Nagano ◽  
Kei Yamana ◽  
Hiroaki Saito ◽  
Riku Kiviranta ◽  
Ana Clara Pedroni ◽  
...  
Keyword(s):  
Bone Density ◽  
Bone Formation ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Erk Signaling ◽  
Canonical Wnt Signaling ◽  
Erk Phosphorylation ◽  
High Bone ◽  
Canonical Wnt

Abstract Activation of Wnt signaling leads to high bone density. The R-spondin family of four secreted glycoproteins (Rspo1-4) amplifies Wnt signaling. In humans, RSPO3 variants are strongly associated with bone density, but how RSPO3 affects skeletal homeostasis is not fully understood. Here we show that in mice Rspo3 haplo-insufficiency or its targeted deletion in osteoprogenitors lead to an increase in bone formation and bone mass. Contrary to expectations, Rspo3 haplo-insufficiency results in canonical Wnt signaling activation. Using mouse embryonic fibroblasts we show that Rspo3 deficiency leads to activation of Erk signaling, stabilizing β-catenin. Furthermore, Rspo3 haplo-insufficiency impairs Dkk1 efficacy in blocking canonical Wnt signaling and prevents the in vivo inhibition of bone formation and bone mass induced by osteoblast-targeted expression of Dkk1. We conclude that Rspo3 haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling and impairing Dkk1’s inhibitory activity, which in turn lead to increased bone formation and bone mass.

scholarly journals Bortezomib induces osteoblast differentiation via Wnt-independent activation of β-catenin/TCF signaling

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4319-4330 ◽  
Author(s):  
Ya-Wei Qiang ◽  
Bo Hu ◽  
Yu Chen ◽  
Ying Zhong ◽  
Bingyin Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Wnt Signaling ◽  
Nuclear Translocation ◽  
Dominant Negative ◽  
Calcium Deposition ◽  
Canonical Wnt Signaling ◽  
Matrix Mineralization ◽  
Canonical Wnt

Abstract Inhibition of Wnt/β-catenin/T-cell factor (TCF) signaling induces proliferation of mesenchymal stem cells and/or suppresses their differentiation into osteoblasts (OBs). Osteolysis in multiple myeloma (MM) is related to the suppression of canonical Wnt signaling caused by DKK1, a soluble inhibitor of this pathway secreted by MM cells. Bortezomib (Bzb) can induce OB differentiation in vitro and in vivo and its anti-MM efficacy linked to bone anabolic effects. However, the molecular basis of the action of Bzb on bone is not completely understood. In the present study, we show that Bzb promotes matrix mineralization and calcium deposition by osteoprogenitor cells and primary mesenchymal stem cells via Wnt-independent activation of β-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting and immunofluorescence, we found that Bzb induced stabilization of β-catenin. Nuclear translocation of stabilized β-catenin was associated with β-catenin/TCF transcriptional activity that was independent of the effects of Wnt ligand-receptor-induced signaling or GSK3β activation. Blocking the activation of β-catenin/TCF signaling by dominant negative TCF attenuated Bzb-induced matrix mineralization. These results provide evidence that Bzb induces OB differentiation via Wnt-independent activation of β-catenin/TCF pathway and suggest that proteasome inhibition therapy in MM may function in part by subverting tumor-induced suppression of canonical Wnt signaling in the bone microenvironment.

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