© 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1418–1424, 2010

Periprosthetic osteolysis: Characterizing the innate immune response to titanium wear‐particles

Christine A. St. Pierre Melvin Chan Yoichiro Iwakura David C. Ayers Evelyn A. Kurt‐Jones Robert W. Finberg

Osteolysis of bone following total hip replacement is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone‐resorption‐inducing cytokine, interleukin 1β (IL‐1β). NALP3, a NOD‐like receptor protein located in the cytosol of macrophages, signals the cleavage of pro‐IL‐1β into its mature, secreted form, IL‐1β. Here we showed that titanium particles stimulate the NALP3 inflammasome. We demonstrated that titanium induces IL‐1β secretion from macrophages. This response depended on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase‐1. We also showed that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response depends on the expression of the IL‐1 receptor and IL‐1α/β. Moreover, administration of the IL‐1 receptor antagonist (IL‐1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particle‐induced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL‐1β secretion and IL‐1‐associated signaling, including neutrophil recruitment. Efficacy of IL‐1Ra treatment introduces the potential for antagonist‐based therapies for implant osteolysis.

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