Bone Abstracts

Wnt/β-catenin signaling, also called canonical Wnt signaling, is important for regulating bone formation. Previous studies reported that deletion of secreted frizzled-related protein (sFRP1), a Wnt antagonist, enhanced trabecular bone accrual in adult mice. Tadalafil, an inhibitor of phosphodiesterase 5 (PDE5), is widely used for treating male erectile dysfunction (ED) in clinical. Inhibition of PDE5 increases cGMP levels and then activates cGMP-dependent protein kinase (PKG). However, whether PDE5 plays a role in regulating canonical Wnt signaling to affect bone formation remains unknown. Here we find that PDE5 inhibitor, Tadalafil, can decrease bone mass through inhibiting canonical Wnt signaling. First, Tadalafil treatment significantly decreased lef1-luciferase activity and β-catenin protein level induced by Wnt3a in 293T without affectingβ-catenin mRNA expression. P33/37/41β-catenin level and GSK3β activity increased following Tadalafil treatment. Also, knockdown of PKG2 increased lef1-luciferase activity and inhibited GSK3β activity. Secondly, Tadalafil treatment decreased ALP activity and osteoblast marker genes expression in C310T1/2. Finally, adult C57 and sFRP1−/− mice had a lower bone mass than control mice after Tadalafil treatment for 2 months. These studies demonstrate that Tadalafil negatively regulating canonical Wnt signaling through GSK3β to decreases bone mass.