Journal article
Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice
M Kansara, M Tsang, L Kodjabachian, NA Sims, MK Trivett, M Ehrich, A Dobrovic, J Slavin, PFM Choong, PJ Simmons, IB Dawid, DM Thomas
Journal of Clinical Investigation | Published : 2009
DOI: 10.1172/JCI37175
Abstract
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 ..
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Awarded by National Institute of Child Health and Human Development
Funding Acknowledgements
The authors would like to thank colleagues in the Bowtell and Thomas laboratories for helpful discussions and Alexander Grinberg, Andreas Tomac, Heiner Westphal, Martha Rebbert, and Paul Love for help in generating gene-modified mice. We thank Carleen Cullinane and staff for PET scanning of the mice. This work was supported by grants 350432 and 508982 from the National Health and Medical Research Council, by the Cancer Council Victoria, by the Sarcoma Foundation of America, by and the intramural Research Program of the NICHD, NIH. D.M. Thomas was supported by R.D. Wright Career Development Award 2003-7 and by Victorian Cancer Agency Clinician Researcher Fellowship 2008-10.