Wnt signaling increases bone mass by stimulating osteoblast lineage commitment and expansion and forms the basis for novel anabolic therapeutic strategies being developed for osteoporosis. These strategies include derepression of Wnt signaling by targeting secreted Wnt pathway antagonists, such as sclerostin. However, such therapies are associated with safety concerns regarding an increased risk of osteosarcoma, the most common primary malignancy of bone. Here, we analyzed 5 human osteosarcoma cell lines in a high-throughput screen for epigenetically silenced tumor suppressor genes and identified Wnt inhibitory factor 1 (WIF1), which encodes an endogenous secreted Wnt pathway antagonist, as a candidate tumor suppressor gene. In vitro, WIF1 suppressed β-catenin levels in human osteosarcoma cell lines, induced differentiation of human and mouse primary osteoblasts, and suppressed the growth of mouse and human osteosarcoma cell lines. Wif1 was highly expressed in the developing and mature mouse skeleton, and, although it was dispensable for normal development, targeted deletion of mouse Wif1 accelerated development of radiation-induced osteosarcomas in vivo. In primary human osteosarcomas, silencing of WIF1 by promoter hypermethylation was associated with loss of differentiation, increased β-catenin levels, and increased proliferation. These data lead us to suggest that derepression of Wnt signaling by targeting secreted Wnt antagonists in osteoblasts may increase susceptibility to osteosarcoma.
Maya Kansara, Michael Tsang, Laurent Kodjabachian, Natalie A. Sims, Melanie K. Trivett, Mathias Ehrich, Alexander Dobrovic, John Slavin, Peter F.M. Choong, Paul J. Simmons, Igor B. Dawid, David M. Thomas
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Nature Reviews Endocrinology | 2013 |
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Development (Cambridge, England) | 2013 |
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The Journal of clinical endocrinology and metabolism | 2012 |
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Cancer Letters | 2012 |
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BMC Systems Biology | 2012 |
The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1's Effects on Wnt and Hedgehog Signaling
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PLoS genetics | 2012 |
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Immunohistochemical investigation of cell cycle and apoptosis regulators (survivin, β-catenin, p53, caspase 3) in canine appendicular osteosarcoma
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BMC veterinary research | 2012 |
Effects of fulvestrant on biological activity and Wnt expression in rat GH3 cells
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Wnt Inhibitory Factor 1 (Wif1) Is Regulated by Androgens and Enhances Androgen-Dependent Prostate Development
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Endocrinology | 2012 |
Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis
KA Fantauzzo, AM Christiano |
Development (Cambridge, England) | 2012 |
Control of bone formation by the serpentine receptor Frizzled-9
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The Journal of Cell Biology | 2011 |
Osteoporosis: now and the future
TD Rachner, S Khosla, LC Hofbauer |
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Emerging Therapeutic Opportunities for Skeletal Restoration
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Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas
U Basu-Roy, E Seo, L Ramanathapuram, TB Rapp, JA Perry, SH Orkin, A Mansukhani, C Basilico |
Oncogene | 2011 |
Wnt signaling is activated at high frequency and drives proliferation of multiple human sarcoma subtypes through a TCF/β-catenin target gene, CDC25A
S Vijayakumar, G Liu, IA Rus, S Yao, Y Chen, G Akiri, L Grumolato, SA Aaronson |
Cancer Cell | 2011 |
Wnt10b Activates the Wnt, Notch and NFκB Pathways in U2OS Osteosarcoma Cells
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Journal of Cellular Biochemistry | 2011 |
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TJ Stein, KE Holmes, A Muthuswamy, V Thompson, MK Huelsmeyer |
Veterinary and Comparative Oncology | 2011 |
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J PosthumaDeBoer, MA Witlox, GJ Kaspers, BJ van Royen |
Clinical & Experimental Metastasis | 2011 |
Influence of β-catenin small interfering RNA on human osteosarcoma cells
F Zhang, A Chen, J Chen, T Yu, F Guo |
Journal of Huazhong University of Science and Technology [Medical Sciences] | 2011 |
Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1
T Malinauskas, AR Aricescu, W Lu, C Siebold, EY Jones |
Nature Structural & Molecular Biology | 2011 |
Osteosarcomagenesis: Modeling Cancer Initiation in the Mouse
KB Jones |
Sarcoma | 2011 |
Update on Wnt signaling in bone cell biology and bone disease
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G Mazziotti, J Bilezikian, E Canalis, D Cocchi, A Giustina |
Endocrine | 2011 |
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The Journal of molecular diagnostics : JMD | 2011 |
Regulation of breast cancer-induced bone lesions by β-catenin protein signaling
Y Chen, HY Shi, SR Stock, PH Stern, M Zhang |
The Journal of biological chemistry | 2011 |
PRKAR1A is an Osteosarcoma Tumor Suppressor and Defines a Molecular Subclass in Mice
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New Treatment Modalities in Osteoporosis
E Canalis |
Endocrine Practice | 2010 |
Update in new anabolic therapies for osteoporosis
E Canalis |
The Journal of clinical endocrinology and metabolism | 2010 |
ARTEMIS stabilizes the genome and modulates proliferative responses in multipotent mesenchymal cells
SA Maas, NM Donghia, K Tompkins, O Foreman, KD Mills |
BMC Biology | 2010 |
The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging
MR Haussler, CA Haussler, GK Whitfield, JC Hsieh, PD Thompson, TK Barthel, L Bartik, JB Egan, Y Wu, JL Kubicek, CL Lowmiller, EW Moffet, RE Forster, PW Jurutka |
The Journal of Steroid Biochemistry and Molecular Biology | 2010 |
Identification of driver and passenger DNA methylation in cancer by epigenomic analysis
S Kalari, GP Pfeifer |
Advances in genetics | 2010 |
Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone
L Endo-Munoz, A Cumming, S Sommerville, I Dickinson, NA Saunders |
British Journal of Cancer | 2010 |
Sclerostin: Current Knowledge and Future Perspectives
MJ Moester, SE Papapoulos, CW Löwik, RL van Bezooijen |
Calcified Tissue International | 2010 |
Severe polyposis in Apc(1322T) mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5
A Lewis, S Segditsas, M Deheragoda, P Pollard, R Jeffery, E Nye, H Lockstone, H Davis, S Clark, G Stamp, R Poulsom, N Wright, I Tomlinson |
Gut | 2010 |
The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition
DS Yee, Y Tang, X Li, Z Liu, Y Guo, S Ghaffar, P McQueen, D Atreya, J Xie, AR Simoneau, BH Hoang, X Zi |
Molecular Cancer | 2010 |
Wnt Inhibitory Factor 1 Decreases Tumorigenesis and Metastasis in Osteosarcoma
EM Rubin, Y Guo, K Tu, J Xie, X Zi, BH Hoang |
Molecular cancer therapeutics | 2010 |
Matrix Metalloproteinase (MMP)-13 Regulates Mammary Tumor–Induced Osteolysis by Activating MMP9 and Transforming Growth Factor-β Signaling at the Tumor-Bone Interface
KC Nannuru, M Futakuchi, ML Varney, TM Vincent, EG Marcusson, RK Singh |
Cancer research | 2010 |
Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells.
Leow PC, Tian Q, Ong ZY, Yang Z, Ee PL |
Investigational New Drugs | 2010 |
Wnt therapy for bone loss: golden goose or Trojan horse?
Greg H. Enders |
Journal of Clinical Investigation | 2009 |
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |
Growth factor control of bone mass
E Canalis |
Journal of Cellular Biochemistry | 2009 |
Promising bone-related therapeutic targets for rheumatoid arthritis
Y Choi, JR Arron, MJ Townsend |
Nature Reviews Rheumatology | 2009 |
Wnt antagonists: for better or worse?
RJ Lories, FP Luyten |
Nature Reviews Rheumatology | 2009 |
Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfβ in osteosarcoma cells
IA san Martin, N Varela, M Gaete, K Villegas, M Osorio, JC Tapia, M Antonelli, EE Mancilla, BP Pereira, SS Nathan, JB Lian, JL Stein, GS Stein, AJ van Wijnen, M Galindo |
Journal of Cellular Physiology | 2009 |
Wnt modulators in the biotech pipeline
JP Rey, DL Ellies |
Developmental Dynamics | 2009 |
Beyond oncology--application of HPMA copolymers in non-cancerous diseases
XM Liu, SC Miller, D Wang |
Advanced Drug Delivery Reviews | 2009 |