Since the discovery of the Wnt gene over 30 years ago as the Int1 proto-oncogene involved in the pathology of Mouse Mammary Tumor Virus (MMTV), Wnt expression and signal transduction have been identified as critical components in regulating embryogenesis, cell proliferation, and bone, glucose, and lipid metabolism. Perturbations in Wnt expression, surface receptors, signaling partners (including β-catenin and GSK-3β), and the battery of Wnt-regulated genes (collectively the canonical Wnt pathway) are known to manifest in a variety of clinically relevant disease states, including cancer, osteoporosis, cardiovascular disease, diabetes, and neurodegeneration.
The concept of turning Wnt signaling down or up, like the dial of a thermostat, to compensate for signaling anomalies is an attractive approach for development of therapeutics. The design and implementation of such therapeutics must be carefully rationalized to identify drugs and regimens that deliver the desired activation or inhibition of Wnt signaling without triggering undesirable side-effects associated with tuning the pathway past a point of normal physiology.