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

摘要

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.