title: Pan-caspase inhibition suppresses polyethylene particle-induced osteolysis.
abstract: Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. Earlier studies demonstrated apoptotic macrophages, giant cells, fibroblasts and T-lymphocytes in capsules and interface membranes of patients with aseptic hip implant loosening. The aim of the current study was to determine in a murine calvarial model of wear particle-induced osteolysis whether inhibition of apoptosis using the pan-caspase inhibitor BOC-D-FMK reduces aseptic loosening. Healthy 12-week-old male C57BL/6J mice were treated with UHMWPE particles and received a daily peritoneal injection of BOK-D-FMK, respectively only buffer at a dose of 3 mg/kg of body weight for 12 days until sacrifice. Bone resorption was measured by histomorphometry, micro CT (computed tomography) and TRAP-5b serum analysis. Apoptosis was measured using caspase-3 cleaved staining. The results demonstrated that UHMWPE particles induced stronger apoptotic reactions in macrophages and osteoblasts and increased bone resorption in non-specifically treated mice, whereas peritoneal application of BOC-D-FMK significantly counteracted these adverse particle-related effects. We think that in particle-induced osteolysis apoptosis is pathologically increased, and that failure to reduce the quantity of apoptotic bodies leads to an up-regulation of proinflammatory cytokines, which may be responsible for the induction of osteolysis. We showed for the first time in vivo that a reduction in apoptosis leads to a significant reduction in particle-induced osteolysis. Clinically, the apoptotic cascade could become an interesting novel therapeutic target to modulate particle-induced osteolysis.
authors.affiliation: Department of Orthopaedics, University of Duisburg-Essen, Pattbergstrasse 1-3, 45239 Essen, Germany. stlandy@t-online.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Landgraeber
authors.forename: Sandra
authors.initials: S
authors.lastname: Jaeckel
authors.forename: Franz
authors.initials: F
authors.lastname: Löer
authors.forename: Christian
authors.initials: C
authors.lastname: Wedemeyer
authors.forename: Gero
authors.initials: G
authors.lastname: Hilken
authors.forename: Ali
authors.initials: A
authors.lastname: Canbay
authors.forename: Martin
authors.initials: M
authors.lastname: Totsch
authors.forename: Marius
authors.initials: M
authors.lastname: von Knoch
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010014:Osteolysis / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D011095:Polyethylenes; D019919:Prosthesis Implantation; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D000071681:Tartrate-Resistant Acid Phosphatase; D055114:X-Ray Microtomography
chemical_list: D001593:Benzyl Compounds; C476029:Boc-D-FMK; D061945:Caspase Inhibitors; D006845:Hydrocarbons, Fluorinated; D007527:Isoenzymes; D011095:Polyethylenes; C111601:ultra-high molecular weight polyethylene; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D053148:Caspase 3