Strontium-modified titanium substrate promotes osteogenic differentiation of MSCs and implant osseointegration via upregulating CDH2.

Cadherin-mediated cell-cell adhesion and signaling are critical for morphogenesis during skeletal development, but its role in the osteogenesis triggered by biomaterials is poorly understand. While our previous studies showed that strontium (Sr)-modified sand-blasted, large grit, acid etched titanium surface (Sr-SLA) is beneficial for osseointegration, the supporting mechanisms have not been explored in detail. In this study, transcriptome analysis of peri-implant bone tissue was performed, and N-cadherin (CDH2) was selected as a key mediator of Sr-SLA-mediated osseointegration. In vitro validation experiments have confirmed that indeed, CDH2 expression in MSCs on Sr-SLA was higher than the control group, which was in parallel with the enhanced cell migration, adhesion, and upregulation of early osteogenic markers. Knocking down CDH2 in MSCs resulted in decreased cell viability and osteogenic differentiation, and the elevated biocompatibility and osteoinductive effect of Sr-SLA were greatly diminished. Surprisingly, Sr-SLA-induced upregulation of CDH2 was not followed by restriction of β-catenin signaling because Sr-SLA also promoted the expression and nuclear translocation of β-catenin. In vivo, a recombinant adeno-associated virus 9 vector carrying an artificial siRNA that target CDH2 (AAV9-CDH2i) was intravenously injected in mice, followed by tibial surgery with implant placement. Accordingly, systemic administration of AAV9-CDH2i effectively knocked down CDH2 expression in bone marrow cells, and in turn, inhibited bone formation induced by Sr-SLA. The results indicated that CDH2 is required for Sr-SLA-mediated bone regeneration, which reveals a new mechanism to explain the osteoinductive effect of Sr-SLA. Thus, biomaterial modifications targeting CDH2 may help improve early osseointegration and bone healing.