Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice
Maya Kansara, … , Igor B. Dawid, David M. Thomas
Maya Kansara, … , Igor B. Dawid, David M. Thomas
Published March 23, 2009
Citation Information: J Clin Invest. 2009;119(4):837-851. https://doi.org/10.1172/JCI37175.
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Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice

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 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.

Authors

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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Figure 6

Wif1–/– mice are susceptible to spontaneous and radiation-induced osteosarcoma.

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Wif1–/– mice are susceptible to spontaneous and radiation-induced osteo...
(A) Left: Sarcoma from the hind left limb of an 89-wk-old male Wif1–/– mouse, arising adjacent to periosteum, and infiltrating skeletal muscle. The adjacent cortical bone (black arrow) and skeletal muscle fiber surrounded by sarcoma cells (red arrow) are indicated. Right: Osteosarcoma from the lumbar spine of a 56-wk-old female Wif1–/– mouse, showing a malignant osteoid (yellow arrow). Scale bars: 100 μm. (B) Radiation-induced osteosarcoma model schematic. (C) Typical imaging appearance of osteosarcomas. Top: 18F-PET scan demonstrating intense avidity of osteoblastic tumors from the same mouse. Bottom: Histology of mouse radiation-induced osteosarcoma. Original magnification, ×20. (D and E) Kaplan-Meier plots of tumor onset (D; P = 0.0032, Mantel-Cox) and survival (E; P = 0.0382, Mantel-Cox) of Wif1–/– and WT mice after exposure to 45Ca (n = 23 [WT]; 22 [Wif1–/–]). (E) Data points represent individual mice; horizontal bars and error bars denote mean ± SEM.