Cyclic Stretch Enhances Osteogenic Differentiation of Human Periodontal Ligament Cells via YAP Activation

Abstract

Periodontal remodeling and alveolar bone resorption and formation play essential roles during orthodontic tooth movement (OTM). In the process, human periodontal ligament cells (HPDLCs) sense and respond to orthodontic forces, contributing to the alveolar bone formation. However, the underlying mechanism in this process is not fully elucidated. In the present study, cyclic stress stimulus was applied on HPDLCs to mimic the orthodontic forces during OTM. Our results demonstrated that cyclic stretch promoted the osteogenic differentiation of HPDLCs. Moreover, our data suggested that yes-associated protein (YAP), the Hippo pathway effector, which also involved in mechanical signaling transduction, was activated as we found that the nuclear translocation of YAP was significantly increased in the cyclic stress treated HPDLCs. The mRNA expression of CTGF and CYR61, the target genes of YAP, was also remarkably increased. Furthermore, knockdown of YAP suppressed the cyclic stretch induced osteogenesis in HPDLCs, while overexpression of YAP in HPDLCs enhanced osteogenesis. We also noticed that YAP activities could be suppressed by the ROCK and nonmuscle myosin II inhibitors, Y-27632 and Blebbistatin. The inhibitors also significantly inhibited the cyclic stretch induced osteogenesis in HPDLCs. Finally, in the murine OTM model, our results revealed that YAP was upregulated and nuclearly translocated in the PDLCs at the tension side. In summary, our present study demonstrated that cytoskeleton remodeling induced activation of YAP signaling pathway was crucial for the cyclic stretch-induced osteogenesis of HPDLCs, which might play important roles during OTM.