Nanotopography on titanium promotes osteogenesis via autophagy-mediated signaling between YAP and β-catenin

Nanostructured titanium implants are recognized for inducing osteogenesis, but the cell signal transductions related to topography are not fully understood. Implant topography is associated with the functionality of osteogenic transcription factors directed by β-catenin in the nucleus, and autophagic flux in the cytoplasm; YAP (Yes-associated protein) is implicated in the destruction of β-catenin in the cytoplasm and is susceptible to autophagic flux. This study investigated whether surface topography of the titanium implant modulates autophagy-lysosome degradation of cytoplasmic YAP. Titanium surfaces were modified with smooth, micro, or nanotopographies. Compared with the smooth and micro surfaces, nanotopography was associated with higher β-catenin nuclear translocation, osteogenic differentiation, and autophagy, and less cytoplasmic YAP. Blockade of the autophagy-lysosome pathway resulted in YAP retention in MC3T3-E1 cells. Cytoplasmic YAP restricted β-catenin nuclear translocation. In the nano surface group, β-catenin accumulation in the nucleus and expression of osteogenesis genes was improved. However, in the absence of cell-cell (confluent) contact, manipulation of YAP and β-catenin localization associated with topography-induced autophagy was lost. In summary, the osteogenesis observed in response to titanium implants with nanotopography involves a signaling link between YAP and β-catenin. STATEMENT OF SIGNIFICANCE: Titanium with rough topographical surfaces is extensively applied in orthopedic and dental clinics. However, the cellular response to topographies that promotes osteogenesis and underlying mechanisms are not fully understood. In this study, we modified titanium surfaces to produce smooth, micro, or nano topographies. Experiments indicated that the nanotopography induced a stronger autophagic response, leading to degraded cytoplasmic YAP. With the lower levels of YAP, β-catenin transported and accumulated in the nucleus to activate TCF/LEF transcription factors, resulting in stronger osteogenesis. Additionally, cell-cell contact was essential in the autophagy-mediated signaling link between YAP and β-catenin. Consequently, our investigation revealed a novel signal transduction in nanotopography-regulated osteogenesis, and supports the modification of biomaterial surfaces to maximize osseointegration.