title: Periprosthetic osteolysis: characterizing the innate immune response to titanium wear-particles.
abstract: 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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Lazare Research Building, Room 228, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: St Pierre
authors.forename: Melvin
authors.initials: M
authors.lastname: Chan
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: David C
authors.initials: DC
authors.lastname: Ayers
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
mesh_terms: D000818:Animals; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration; D010014:Osteolysis / Q000209:etiology* / Q000276:immunology; D014025:Titanium / Q000276:immunology* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D007375:Interleukin-1; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014025:Titanium