Abstract
The canonical Wnt signaling pathway, in which β-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 β-catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear β-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 β-catenin in the nucleus. The isomerized β-catenin could not bind to nuclear adenomatous polyposis coli, which drives β-catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of β-catenin in the nucleus and might explain the decrease of β-catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate β-catenin-mediated osteogenesis.
Highlights
prolyl cistrans isomerase NIMA-interacting 1 (Pin1) Controls -Catenin Protein Stability and Wnt3a-induced Transactivation Activity—In this context, we aimed to characterize the role of Pin1 in adult bone metabolism through canonical Wnt signaling
Brown -catenin expression spots were identified in osteoblasts of the WT, whereas spots were difficult to identify in the Pin1 KO counterpart (Fig. 1A)
Because previous reports have indicated that Pin1 action influences substrate protein stability, we suspected that the decrease in -catenin protein level in Pin1 KO mice was a result of decreased protein stability
Summary
We have found previously that the interaction of Pin with Runx, the major transcription factor for osteoblast differentiation, is critical for bone development [25, 26]. Pin is known to bind and modulate -catenin stability and subcellular localization at the posttranslational level by regulating its interaction with APC in breast cancer [21] and neuronal differentiation [22]. It is not known whether Pin is related to the regulation of osteoblast differentiation by -catenin modulation or, if so, which detailed molecular mechanisms control this process. Our results reveal that Pin is a novel regulator that promotes osteoblast differentiation through structural modification and stabilization of -catenin in the nucleus
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