Objective To evaluate the mechanisms of p42/p44 kinase phosphorylation in cell models and to investigate the effect of simvastatin on the prevention and treatment of aseptic loosening of prosthesis by observing the influence of simvastatin on the levels of tumor necrosis factor α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) of human peri pheral blood mononuclear cell (PBMC) challenged with titanium particles. Methods PBMC from 45 mL peripheral blood of healthy adult voluntary donators, were separated and cultured, and divided into 5 groups according to different culturemedium: group A, PBMC and titanium particles; group B, PBMC and titanium particles with 1 × 10-5 mol/L simvastatin; group C, PBMC and titanium particles with 1 × 10-6 mol/L simvastatin; group D, PBMC and titanium particles with 1 × 10-7 mol/L simvastatin; and group E, PBMC and titanium particles with the extracellular signal-regulated kinase (ERK1/2) inhibitor U0126. The contents of TNF-α and MCP-1 were tested by ELISA after 24 hours of culture. PBMC were pretreated with different medium grouping as groups A, B, C, D, and E for 60 minutes, and were challenged with titanium particles for 30 minutes and 60 minutes, then the level of ERK1/2 expression was tested by Western blot. Results In groups A, B, C, D, and E, the absorbance (A) values of TNF-α were 1.115 5 ± 0.243 6, 0.693 6 ± 0.354 3, 0.695 7 ± 0.387 3, 0.716 4 ± 0.478 9, and 0.263 5 ± 0.101 6, respectively; and the A values of MCP-1 were 1.421 0 ± 0.105 3, 0.915 1 ± 0.411 3, 1.003 5 ± 0.464 2, 1.102 0 ± 0.353 9, and 0.271 3 ± 0.145 1, respectively. The levels of TNF-α and MCP-1 in group A were significantly higher than others, showing significant differences (P lt; 0.05). There were significant differences between group E and groups B, C, and D (P lt; 0.05), between group B and groups C, D (P lt; 0.05); no significant difference between group C and group D (P gt; 0.05). Western blot results showed the expression of ERK1/2 in all groups at 30 minutes and 60 minutes of culture. The levels of ERK1/2 expression were 1.612 1 ± 0.068 2, 1.078 1 ± 0.072 8, 1.268 7 ± 0.223 1, 1.439 7 ± 0.180 1, and 0.732 0 ± 0.110 4 in groups A, B, C, D, and E, respectively; showing significant differences between groups (P lt; 0.05). Conclusion ERK1/2 is a phosphorylated protein after stimulated by wear particles; it is also one of the most important cell signal ing activation of macrophage. Simvastatin can inhibit the expression of bone absorptive factors induced by wear particles and may be used in the prevention and treatment of aseptic loosening of prosthesis.