The periprosthetic osteolysis induced by wear particles contributes to aseptic loosening after joint arthroplasty. The molecular mechanism underlying osteolysis remains to be described. In this study, cultured MC3T3-E1 cells were incubated with titanium particles. We investigated the role of p38 mitogen-activated protein kinase in the expression of MMP-2 in response to wear particles. Our results demonstrated MC3T3-E1 cells exposed to titanium particles had significantly increased levels of MMP-2 and MT1-MMP mRNA, whereas the TIMP-2 mRNA level was unchanged. In MC3T3-E1 cells, the protein expression of MMP-2, MT1-MMP, and active p38 was also elevated after titanium particle exposure, as detected by Western blot and Biotrak activity analyses. Inhibition studies showed that the specific p38 inhibitor SB203580 completely abrogated the increase in MMP-2 and MT1-MMP production induced by the titanium particles. Moreover, our results revealed that conditioned mediastimulated osteoclast formation was related to the MMP-2 activity of osteoblasts that were challenged with Ti particles. This study demonstrated that p38 signaling is required for MMP-2 activity in osteoblasts under wear particle-induced conditions. MMP-2 could act as a catabolic element or a proinflammatory factor contributing to periprosthetic osteolysis. Therefore, the p38 pathway and MMP-2 may play a critical role in the development of aseptic loosening. (C) 2013 Wiley Periodicals, Inc.