Previous studies have found that microRNA-21 (miR-21) is an important functional factor during osteoclast differentiation. Abnormal osteoclastogenesis induced by wear particles is the main cause of aseptic loosening in joint replacements. The aim of the present study is to investigate the possible role of miR-21 in the pathogenesis of particle-induced osteolysis (PIO). miR-21 expression was examined in a PIO mouse model using real-time (RT-PCR). Osteoclastogenesis was determined by a tartrate resistant acid phosphatase (TRAP) quantification method. A toluidine blue staining assay was used to examine calvarial osteolysis. The results demonstrated that miR-21 was significantly upregulated in the PIO animal model. Knocking out miR-21 in the particle-stimulated tissue could ameliorate osteolysis symptoms. Additionally, through our analysis of PDCD4 and AP-1 expression, we suggest that the feedback loop of AP-1, miR-21, and PDCD4 might have an important influence on the development of PIO and that miR-21 is a potential target for implant loosening therapies.