title: Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation.
abstract: Activation of myeloid cells by orthopedic particulate debris is a key event in the pathogenesis of periprosthetic osteolysis and implant loosening after total joint replacement (TJR). Several lines of evidence implicate NACHT, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome-mediated production of interleukin 1 beta (IL-1β) in the pathogenesis of clinical disorders ascribable to foreign particulate materials, including asbestos, silica, and urate crystals. Recent reports indicate that orthopedic polymer products and metallic particulates and ions may activate the same pathway. Here, we investigated the contribution of the NALP3 inflammasome to the pathogenesis of peri-implant osteolysis. Pharmaceutical and genetic perturbations of caspase-1 and inflammasome components were used to assess the role of the NALP3 inflammasome in IL-1β production and osteoclast formation by human monocytes and mouse macrophages in response to polymethylmethacrylate (PMMA) particle phagocytosis. The role of caspase-1 in a mouse calvarial model of particle-mediated osteolysis was assessed using µCT. Phagocytosis of PMMA particles induces caspase-1 dependent release of IL-1β from human monocytes and mouse macrophages. Importantly, using macrophages from mice deficient in components of the NALP3 inflammasome, we show PMMA-induced IL-1β production is strictly dependent on these components. Mice lacking caspase-1, the sole effector of the NALP3 inflammasome, show reduced orthopedic wear particle-induced calvarial osteolysis compared to wild-type controls. Absence of NALP3 inflammasome components fails to alter osteoclast formation in vitro. Our findings identify the NALP3 inflammasome as a critical mediator of orthopedic wear-induced osteolysis and as a viable therapeutic target for the treatment of periprosthetic osteolysis.
authors.affiliation: Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, USA.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Burton
authors.forename: Daniel
authors.initials: D
authors.lastname: Paget
authors.forename: Nikolaus B
authors.initials: NB
authors.lastname: Binder
authors.forename: Krista
authors.initials: K
authors.lastname: Bohnert
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Nestor
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sculco
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldring
authors.forename: P Edward
authors.initials: PE
authors.lastname: Purdue
mesh_terms: D000818:Animals; D019643:Arthroplasty, Replacement / Q000009:adverse effects*; D001843:Bone Cements / Q000633:toxicity; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D020169:Caspases / Q000172:deficiency / Q000235:genetics; D053471:Caspases, Initiator; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010014:Osteolysis / Q000276:immunology* / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D019904:Polymethyl Methacrylate / Q000633:toxicity*; D011475:Prosthesis Failure / Q000209:etiology*; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D012886:Skull / Q000166:cytology / Q000276:immunology
chemical_list: D001843:Bone Cements; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D019904:Polymethyl Methacrylate; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator