In prosthetic loosening, bone resorption is induced by wear debris particles generated from the artificial joint articulation. Our prior work showed that synovial-like fibroblasts respond to titanium particles by producing RANKL (receptor activator of nuclear factor kappa B), a critical activator of osteoclastogenesis. While this effect occurs through a COX-2 (cyclooxygenase-2) dependent pathway, the mechanism of COX-2 stimulation by titanium particles is not clear. Here we show that titanium particles induce COX-2 gene expression by activating NFB (nuclear factor kappa B) signaling. Inhibitor of NFB (IB) is degraded following particle treatment, permitting active NFB to translocate to the nucleus where it interacts with the COX-2 promoter and drives transcription. NFB activation is dependent upon reactive oxygen species since antioxidants block the NFB signaling induced by particles. Surprisingly, IB degradation is independent of IKK (IB kinase) and the 26S proteasome. Instead, calpain inhibitor can block the IB degradation induced by particles. Furthermore, the calpain-targeted C-terminal PEST sequence of IB is necessary for phosphorylation and degradation, consistent with a proteasome independent mechanism of catabolism. Altogether, the data demonstrate a signaling pathway by which titanium particles induce oxidative stress, stimulate calpain-mediated NFB activation, and activate target gene expression, including COX-2. These findings define important targets for osteolysis, but may have importance in other diseases where fibroblasts respond to environmental particles, including pulmonary diseases.