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Wnt therapy for bone loss: golden goose or Trojan horse?
Greg H. Enders
Department of Medicine, Epigenetics and Progenitor Cell Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Address correspondence to: Greg H. Enders, Department of Medicine, W225, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA. Phone: (215) 214-3956; Fax: (215) 728-4333; E-mail: greg.enders@fccc.edu.
Find articles by Enders, G. in: PubMed | Google Scholar
Published March 23, 2009 - More info
J Clin Invest. 2009;119(4):758–760. https://doi.org/10.1172/JCI38973.
© 2009 The American Society for Clinical Investigation
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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
Bone loss is a significant clinical concern. It can be caused by aging or by several diseases and their treatments, such as glucocorticoid hormone therapy for autoimmune disease (1, 2). Hip fracture in the elderly, an important complication of bone loss, carries a 1-year mortality rate of approximately 25% (3, 4). Treatment and prophylaxis of bone loss has focused on supporting bone mineralization and inhibiting bone resorption, but attention has increasingly turned to building bone by augmenting osteoblast function (5, 6). Some drugs under development act in part through stimulating the Wnt signaling pathway, known to drive osteoblast proliferation and commitment (6, 7). In particular, efforts are underway to block the actions of secreted Wnt antagonists such as sclerostin (5). The goal of taking advantage of our burgeoning knowledge of signaling pathways in order to build tissue in general and repair bones in particular has great appeal. The theoretical potential exists for the Wnt pathway to serve as a golden goose, generating new bone indefinitely.
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The Wnt pathway
The Wnt pathway is a workhorse of development in multicellular organisms. It directs fate decisions, big and small, such as forming a principal axis of frog embryo development (8) or sculpting heart valves (9). Wnt signaling often drives tissue formation. This functionality endures in some adult tissues that require continuous replenishment, such as the renewal of the intestinal epithelium (10).
However, the Wnt pathway is also the prototypical developmental pathway deregulated in cancer (11). In fact, the pathway’s name embodies this potential: Wnt is a contraction of Wingless from Drosophila and Int1 from mammals (12). The Wingless gene was discovered as the site of a mutation in Drosophila responsible for defective patterning of the trunk (13). Int1, the first mammalian homolog of Wingless, was discovered as a common site of integration of mouse mammary tumor virus genomes in tumors induced by the virus (14). These insertion events mediate Wnt1 overexpression and tumor growth. The tendency of Wnt deregulation to foster neoplasia is a concern.
The canonical Wnt pathway is liberally endowed with regulatory steps (Figure 1). Wnts, the ligands, are low-abundance secreted factors that are somewhat lipophilic (15, 16). For a long time, Wnts could not be isolated biochemically, even when overexpressed in cell culture. Expression was inferred from their biological effects (16). These properties likely reflect the role of Wnt proteins as short-range paracrine factors, thought to often be present in steep gradients of abundance. Wnt proteins bind 7-pass transmembrane domain receptors of the Frizzled family (11). Such binding is antagonized by the Wnt inhibitory factors (WIFs) and secreted Frizzled-related proteins (SFRPs), which are all secreted proteins that compete with receptors for ligand binding. Ligand binding activates the Frizzled receptors, transducing a signal through the scaffolding protein Dishevelled and Casein kinase 1 to a protein complex that contains the kinase glycogen synthase kinase–3 and the tumor suppressor proteins adenomatous polyposis coli (APC; named for the human genetic disease also termed familial adenomatous polyposis) and axis inhibition protein 1. The APC complex constitutively targets β-catenin for ubiquitination and degradation. The Wnt signal inhibits the APC complex, leading to stabilization of β-catenin and its accumulation in the nucleus. There, β-catenin teams with T cell factor transcription factors to drive expression of genes such as c-Myc and Cyclin D1 that support cell growth, proliferation, and survival. The pivotal role of Wnt signaling in normal and abnormal growth is underscored by the fact that multiple pathway components have been implicated as either oncogenes or tumor suppressors (Figure 1).
Figure 1The Wnt signaling pathway. Wnt ligands bind to transmembrane receptors of the Frizzled family. Secreted factors such as WIFs and SFRPs compete with Wnt ligands for binding. Activated receptor signals through Dishevelled and Casein kinase 1 (CK1) to a protein complex containing glycogen synthase kinase–3 (GSK3), axis inhibition protein 1 (Axin), and APC. The APC complex constitutively directs β-catenin ubiquitination and degradation. The Wnt signal inhibits the APC complex, leading to β-catenin stabilization and accumulation in the nucleus. Nuclear β-catenin binds T cell factor (Tcf) transcription factors to drive expression of genes such as c-Myc and Cyclin D1 that support cell growth, proliferation, and survival. Oncogenes are shown in green; tumor suppressor genes are shown in red. In this issue of the JCI, Kansara et al. provide evidence that WIF1 is a tumor suppressor and that epigenetic silencing of WIF1 accelerates osteosarcomagenesis (17).
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