Pin1-mediated Modification Prolongs the Nuclear Retention of -Catenin in Wnt3a-induced Osteoblast Differentiation

The canonical Wnt signaling pathway, in which -catenin nuclear localization is a crucial step, plays an important role in osteoblast differentiation. Pin1, a prolyl isomerase, is also known as a key enzyme in osteogenesis. However, the role of Pin1 in canonical Wnt signal-induced osteoblast differentiation is poorly understood. We found that Pin1 deficiency caused osteopenia and reduction of -catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear -catenin level, TOP flash activity, and expression of bone marker genes induced by canonical Wnt activation and vice versa in Pin1 overexpression. Pin1 interacts directly with and isomerizes -catenin in the nucleus. The isomerized -catenin could not bind to nuclear adenomatous polyposis coli, which drives -catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of -catenin in the nucleus and might explain the decrease of -catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate -catenin-mediated osteogenesis.