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: Stefan Landgraeber, Sandra Jaeckel, Franz Löer, Christian Wedemeyer, Gero Hilken, Ali Canbay, Martin Totsch, Marius von Knoch
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 14 Issue 2 Pg. 173-81 (Feb 2009) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 19130234 (Publication Type: Journal Article)

Chemical References

• Benzyl Compounds
• Boc-D-FMK
• Caspase Inhibitors
• Hydrocarbons, Fluorinated
• Isoenzymes
• Polyethylenes
• ultra-high molecular weight polyethylene
• Acid Phosphatase
• Acp5 protein, mouse
• Tartrate-Resistant Acid Phosphatase
• Caspase 3

Topics

• Acid Phosphatase (blood)
• Animals
• Benzyl Compounds (pharmacology)
• Caspase 3 (metabolism)
• Caspase Inhibitors
• Hydrocarbons, Fluorinated (pharmacology)
• Immunohistochemistry
• Isoenzymes (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Organ Size
• Osteoclasts (drug effects, pathology)
• Osteolysis (blood, chemically induced, enzymology, prevention & control)
• Polyethylenes
• Prosthesis Implantation
• Skull (diagnostic imaging, drug effects, enzymology, pathology)
• Tartrate-Resistant Acid Phosphatase
• X-Ray Microtomography