In Vivo Analysis of Wnt Signaling in Bone
Department of Genetics and Development, Columbia University, New York, New York, United States Endocrinology
(Impact Factor: 4.5).
06/2007; 148(6):2630-4. DOI: 10.1210/en.2006-1372
Bone remodeling requires osteoblasts and osteoclasts working in concert to maintain a constant bone mass. The dysregulation of signaling pathways that affect osteoblast or osteoclast differentiation or function leads to either osteopenia or high bone mass. The discovery that activating and inactivating mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, led to high bone mass and low bone mass in human beings, respectively, generated a tremendous amount of interest in the possible role of the Wnt signaling pathway in the regulation of bone remodeling. A number of mouse models have been generated to study a collection of Wnt signaling molecules that have been identified as regulators of bone mass. These mouse models help establish the canonical Wnt signaling pathway as a major regulator of chondrogenesis, osteoblastogenesis, and osteoclastogenesis. This review will summarize these advances.
Available from: PubMed Central
- "The application of differentiation therapy for solid tumours has been hindered by the absence of developmental models of cancer progression that correlate cancer subtypes to stages of normal development. Osteosarcoma cells share many similar features to undifferentiated osteoprogenitors including a high proliferative capacity, resistance to apoptosis and similar expression profiles of many osteogenic markers such as connective tissue growth factor, runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osterix and osteocalcin , . Increasing evidence suggests that osteosarcoma cells can be induced to mature osteoblasts by certain compounds, including retinoic acid . "
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ABSTRACT: Osteosarcoma, one of the most common malignant bone tumours, is generally considered a differentiation disease caused by genetic and epigenetic disruptions in the terminal differentiation of osteoblasts. Novel therapies based on the non-cytotoxic induction of cell differentiation-responsive pathways could represent a significant advance in treating osteosarcoma; however, effective pharmaceuticals to induce differentiation are lacking. In the present study, we investigated the effect of hyperoside, a flavonoid compound, on the osteoblastic differentiation of U2OS and MG63 osteosarcoma cells in vitro. Our results demonstrated that hyperoside inhibits the proliferation of osteosarcoma cells by inducing G0/G1 arrest in the cell cycle, without causing obvious cell death. Cell migration assay further suggested that hyperoside could inhibit the invasion potential of osteosarcoma cells. Additionally, osteopontin and runt-related transcription factor 2 protein levels and osteocalcin activation were upregulated dramatically in hyperoside-treated osteosarcoma cells, suggesting that hyperoside may stimulates osteoblastic differentiation in osteosarcoma cells. This differentiation was accompanied by the activation of transforming growth factor (TGF)-β and bone morphogenetic protein-2, suggesting that the hyperoside-induced differentiation involves the TGF-β signalling pathway. To our knowledge, this study is the first to evaluate the differentiation effect of hyperoside in osteosarcoma cells and assess the possible potential for hyperoside treatment as a future therapeutic approach for osteosarcoma differentiation therapy.
PLoS ONE 07/2014; 9(7):e98973. DOI:10.1371/journal.pone.0098973 · 3.23 Impact Factor
Available from: Adriana De Siervi
- "RANKL has been shown to activate mature osteoclasts and mediate osteoclastogenesis. OPG acts as a decoy receptor for RANKL . The co-culture of PMOs and PC3 Hem cells produced an increase in RANKL and a decrease in OPG transcript levels in osteoblasts; the same result was observed after co-culture of PMOs with PC3 control cells (Figure 3 A&B). "
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ABSTRACT: Prostate cancer (PCa) is a leading cause of death among males. It is currently estimated that inflammatory responses are linked to 15-20% of all deaths from cancer worldwide. PCa is dominated by complications arising from metastasis to the bone where the tumor cells interact with the bone microenvironment impairing the balance between bone formation and degradation. However, the molecular nature of this interaction is not completely understood. Heme oxygenase-1 (HO-1) counteracts oxidative damage and inflammation. Previous studies from our laboratory showed that HO-1 is implicated in PCa, demonstrating that endogenous HO-1 inhibits bone derived-prostate cancer cells proliferation, invasion and migration and decreases tumor growth and angiogenesis in vivo. The aim of this work was to analyze the impact of HO-1 modulated PCa cells on osteoblasts proliferation in vitro and on bone remodeling in vivo. Using a co-culture system of PC3 cells with primary mice osteoblasts (PMOs), we demonstrated that HO-1 pharmacological induction (hemin treatment) abrogated the diminution of PMOs proliferation induced by PCa cells and decreased the expression of osteoclast-modulating factors in osteoblasts. No changes were detected in the expression of genes involved in osteoblasts differentiation. However, co-culture of hemin pre-treated PC3 cells (PC3 Hem) with PMOs provoked an oxidative status and activated FoxO signaling in osteoblasts. The percentage of active osteoblasts positive for HO-1 increased in calvarias explants co-cultured with PC3 Hem cells. Nuclear HO-1 expression was detected in tumors generated by in vivo bone injection of HO-1 stable transfected PC3 (PC3HO-1) cells in the femur of SCID mice. These results suggest that HO-1 has the potential to modify the bone microenvironment impacting on PCa bone metastasis.
PLoS ONE 11/2013; 8(11):e80315. DOI:10.1371/journal.pone.0080315 · 3.23 Impact Factor
Available from: Ana López-Herradón
- "This protein activates canonical Wnt/β-catenin pathway [Ling et al., 2010], and its expression has been shown to occur related to osteoblast differentiation [Bain et al., 2003; Cho et al., 2009]. Wnt proteins signal by interacting with a cell membrane receptor complex comprising the Fzd family of receptors and co-receptors LRP-5 and LRP-6 [Glass and Karsenty, 2007; Mao et al., 2001a; Mao et al., 2001b]. A clear relationship exists between these co-receptors and the maintenance of bone mass as revealed by gain-or loss-of-function mutations affecting LRP-5 and LRP-6 genes in both mice and humans [Bodine and Komm, 2006]. "
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ABSTRACT: Recent in vivo findings suggest that the bone sparing capacity of parathyroid hormone-related protein (PTHrP) in diabetic mice might be due at least in part through targeting a suppressed Wnt/β-catenin pathway in osteoblasts. We here aimed to examine the inhibitory action of a high glucose environment on specific components of the canonical Wnt pathway, and the putative compensatory effects of PTHrP, in osteoblastic cell cultures. Mouse osteoblastic MC3T3-E1 cells and primary cultures of fetal mouse calvaria were exposed to normal (5.5 mM) or high (25 mM) D-glucose (HG), with or without PTHrP (1-36) or PTHrP (107-139) for different times. In some experiments, MC3T3-E1 cells were incubated with the Wnt pathway activators Wnt3a and LiCl, or were transfected with plasmids encoding either a mutated β-catenin that cannot be targeted for degradation or a human PTHrP (-36/+139) cDNA, or the corresponding empty plasmid, in the presence or absence of HG. The gene expression of Wnt3a and low density receptor-like proteins (LRP)-5 and 6, as well as β-catenin protein stabilization and β-catenin-dependent transcription activity were evaluated. Oxidative stress status under HG condition was also assessed. The present data demonstrate that HG can target different components of the canonical Wnt pathway, while β-catenin degradation appears to be a key event leading to inhibition of Wnt/β-catenin signalling in mouse osteoblastic cells. Both PTHrP peptides tested were able to counteract this deleterious action of HG. These in vitro findings also provide new clues to understand the underlying mechanisms whereby PTHrP can increase bone formation. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry 08/2013; 114(8). DOI:10.1002/jcb.24535 · 3.26 Impact Factor
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