Orthopedic Implant Particle-Induced Tumor Necrosis Factor-α Production in Macrophage–Monocyte Lineage Cells Is Mediated by Nuclear Factor of Activated T Cells

: Wear particles produced from artificial joint prostheses are known to cause macrophage–monocyte lineage cells to produce proosteoclastogenic cytokines, including tumor necrosis factor (TNF)-α. The specific molecular mechanism, however, is not yet known. Bioinformatic analysis showed that the promoter region of TNF-α has several consensus sequences for NFAT binding. Consequently, we examined the role of nuclear factor of activated T cells (NFAT) in TNF-α production. Our investigation has shown that treatment with titanium nanoparticles increased TNF-α gene expression along with TNF-α protein secretion in murine macrophage-like RAW264.7 and primary monocyte–macrophage cells. Titanium particle-induced TNF-α induction was inhibited by VIVIT, a peptide inhibitor that targets the calcineurin/NFAT axis, which suggests that NFAT mediates metallic particle-induced TNF-α expression in monocyte–macrophage lineage cells.