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.

Bone turnover markers correlate with implant fixation in a rat model using LPS‐doped particles to induced implant loosening

“…It is known that LPS can be present in periprosthetic tissue of patients with loosened implants but in whom there is no clinical or microbiological evidence of infection 36 . Endotoxin contamination of orthopedic implants and wear debris is common and appears to be an important component of biological activity 37 . In our study, there was no bacteriological evidence of infection, suggesting that this can be considered a model of aseptic loosening.…”

The Pathology of Orthopedic Implant Failure Is Mediated by Innate Immune System Cytokines

“…This in vitro evidence has been supported by in vivo immunohistochemistry of central apoptosis-related mediators such as caspase-3 associated with macrophages, giant cells, and T-lymphocytes in local tissues (capsules and interfacial membranes) of patients with aseptic hip implants [55, 56]. The importance of apoptosis associated mediators has been made clear by murine osteolysis models that demonstrated inhibition of apoptosis by a pan-caspase inhibitor leads to decreasing bone resorption by osteoclasts [57] and presumably decreased amounts of apoptosis associated cytokines like interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1, and type-1 interferon [58, 59]. …”

Chemokines Associated with Pathologic Responses to Orthopedic Implant Debris

“…The induction of apoptosis-like responses associated with implant debris has also been correlated with implant debris in vivo , such as caspase-3 associated with macrophages, giant cells, and T-lymphocytes in local tissues (capsules and interfacial membranes) of patients with aseptic hip implants (59). But, it is important not to confuse apoptosis with that of danger signaling and other inflammatory pathways because early studies using pan-caspase inhibitors (which inhibit danger signaling) erroneously concluded that inhibition of apoptosis by a pan-caspase inhibitors mitigates implant-induced inflammation osteolysis (60), when in fact it was the pan-caspase inhibition of inflammation pathways that decreased inflammation (8, 11). The role of apoptosis, pyroptosis, and pyronecrosis in implant-induced inflammation is still unclear and controversial.…”