Pan-caspase inhibition suppresses polyethylene particle-induced osteolysis |
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Authors: | Stefan Landgraeber Sandra Jaeckel Franz Löer Christian Wedemeyer Gero Hilken Ali Canbay Martin Totsch Marius von Knoch |
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Institution: | (1) Department of Orthopaedics, University of Duisburg-Essen, Pattbergstrasse 1–3, 45239 Essen, Germany;(2) Central Animal Laboratory, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany;(3) Department of Gastroenterology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany;(4) Institute of Pathology and Neuropathpology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany |
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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 proinflammtory 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.
This is an investigation performed at the University of Duisburg-Essen, Germany. |
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Keywords: | Apoptosis Wear debris Endoprosthesis Osteolysis |
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