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Micro/nanotopographies (MNTs) have been reported to enhance the osseointegration of biomaterials and modulate cell functions, but the underlying mechanisms are incompletely understood. We hypothesized that transient receptor potential vanilloid 4 (TRPV4) may mediate the topographically induced osteoblastic differentiation of bone marrow stem cells (BMSCs) by regulating the NFATc1 and Wnt/β-catenin signaling. To test this hypothesis, murine BMSCs were cultured on polished titanium (Ti) discs (PT) and Ti discs carrying titania nanotubes (i.e., MNTs) with diameters of ∼30 and ∼100 nm (termed TNT-30 and TNT-100, respectively). It was found that the MNTs (in particular TNT-100) promoted the expression and activation of TRPV4. Inhibition of TRPV4 in BMSCs cultured on TNT-100 reduced the expression of osteoblastic genes and the gene expression and protein levels of NFATc1 and Wnt3a/β-catenin and also decreased nuclear translocation of NFATc1 and β-catenin (all vs uninhibited BMSCs). Conversely, activation of TRPV4 in BMSCs cultured on PT increased the expression of the osteoblastic gene and the gene expression and protein level of NFATc1 and Wnt3a/β-catenin and also enhanced the nuclear translocation of NFATc1 and β-catenin (all vs unactivated BMSCs). These differences suggest that the MNTs promoted TRPV4 expression and activation to enhance intracellular Ca2+, which further increased the nuclear translocation of NFATc1 and stimulated the Wnt/β-catenin signaling, thus leading to upregulated expression of osteoblastic genes. These results indicate TRPV4 to be a mediator in MNT-induced osteoblastic differentiation of BMSCs.

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