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RECEPTORS AND SIGNAL TRANSDUCTION

Titanium particles stimulate COX-2 expression in synovial fibroblasts through an oxidative stress-induced, calpain-dependent, NF-B pathway

Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York

Submitted 21 November 2008 ; accepted in final form 1 June 2009

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 receptor activator of NF-B ligand (RANKL), a critical activator of osteoclastogenesis. While this effect occurs through a cyclooxygenase-2 (COX-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 NF-B signaling. Inhibitor of NF-B (IB) is degraded following particle treatment, permitting active NF-B to translocate to the nucleus where it interacts with the COX-2 promoter and drives transcription. NF-B activation is dependent on reactive oxygen species since antioxidants block the NF-B 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 COOH-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 NF-B activation, and activate target gene expression, including COX-2. These findings define important targets for osteolysis but may also have importance in other diseases where fibroblasts respond to environmental particles, including pulmonary diseases.

cyclooxygenase-2; osteolysis; inflammation; cell signaling; reactive oxygen species