title: Endosomal damage and TLR2 mediated inflammasome activation by alkane particles in the generation of aseptic osteolysis.
abstract: Ultra-high molecular weight polyethylene is widely used as a bearing surface in prosthetic arthroplasty. Over time the generation of implant-derived wear particles can initiate an inflammatory reaction characterized by periprosthetic inflammation and ultimately bone resorption at the prosthetic bone interface. Herein we present evidence that the different sized particles as well as the different length alkane polymers generated by implant wear leads to a two component inflammatory response. Polymeric alkane structures, with side chain oxidations, directly bind and activate the TLR-1/2 signaling pathway. Whereas micron- and nanometer-sized particulate debris are extensively phagocyted and induce enlargement, fusion and disruption of endosomal compartments. The resulting lysosomal damage and subsequent enzymatic leakage induces the NALP3 inflammasome activation as determined by cathepsins S and B cytosolic release, Caspase 1 activation and processing of pro-IL-1beta, and pro-IL-18. These two processes synergistically results in the initiation of a strong inflammatory response with consequent cellular necrosis and extracellular matrix degradation.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Radhashree
authors.initials: R
authors.lastname: Maitra
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Clement
authors.forename: Brian
authors.initials: B
authors.lastname: Scharf
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Crisi
authors.forename: Sriram
authors.initials: S
authors.lastname: Chitta
authors.forename: Daniel
authors.initials: D
authors.lastname: Paget
authors.forename: P Edward
authors.initials: PE
authors.lastname: Purdue
authors.forename: Neil
authors.initials: N
authors.lastname: Cobelli
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
mesh_terms: D000473:Alkanes / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D001207:Asepsis; D003094:Collagen / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D011992:Endosomes / Q000473:pathology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D015726:Giant Cells / Q000187:drug effects / Q000276:immunology; D006622:Hip Prosthesis; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000276:immunology* / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010014:Osteolysis / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D010316:Particle Size; D011095:Polyethylenes / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D000473:Alkanes; D011095:Polyethylenes; D011108:Polymers; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; C111601:ultra-high molecular weight polyethylene; D003094:Collagen