Titanium dioxide nanotubes of defined diameter enhance mesenchymal stem cell proliferation via JNK- and ERK-dependent up-regulation of fibroblast growth factor-2 by T lymphocytes

Long-term clinical success of a titanium implant not only depends upon osseointegration between implant and bone surface but also on the response of host immune cells. Following implantation of biomaterials, an inflammatory response, including T lymphocyte response, is ostensibly initiated by implant-cell interaction. However, little is known about the responses of T lymphocytes to titanium dioxide nanotubes. The present study aimed to explore the effect of titanium dioxide nanotubes on T lymphocytes in vitro and its biological consequences. The results of the present study showed that titanium dioxide nanotubes with diameter of 30–105 nm were non-cytotoxic to T lymphocytes, and the 105 nm titanium dioxide nanotube surface specifically possessed an ability to activate T lymphocytes, thus increasing DNA synthesis and cell proliferation. In addition, the 105 nm titanium dioxide nanotubes significantly activated the expression of FGF-2 gene and protein in T lymphocytes although smaller nanotubes (i.e. those with diameters of approximately 30 and 70 nm) had little effect on this. The present study investigated the mechanism by which 105 nm nanotubes stimulated FGF-2 expression in T lymphocytes by blocking key MAPK pathways. The inhibitors of JNK1/2/3 and ERK1/2 significantly inhibited 105 nm titanium dioxide nanotubes-induced FGF-2 expression. Corresponding to the increased expression of FGF-2, only the supernatant from T lymphocytes cultured on 105 nm nanotubes stimulated human mesenchymal stem cell proliferation. FGF-2 blocking antibody partially reversed the increased proliferation of human mesenchymal stem cells, supporting the role of T lymphocyte-derived FGF-2 in enhanced human mesenchymal stem cell proliferation. This suggests a significant role of T lymphocyte-titanium dioxide nanotube interaction in the proliferation of human mesenchymal stem cells, which is pivotal to the formation of new bone following implant placement.