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8th Combined Meeting Of Orthopaedic Research Societies (CORS)



Wear particles from joint replacements may result in loosening and periprosthetic osteolysis. Interference with systemic macrophage trafficking to the implant, modulation of macrophage phenotype from M1 to M2, and inhibition of NFκB may mitigate these adverse effects.


Joint replacement of the lower extremity is highly successful in alleviating pain, and improving ambulation and function. However, prosthetic byproducts of different materials, in sufficient amounts, may lead to loosening and periprosthetic osteolysis. Debris from polymers (such as polyethylene and PMMA), metals and ceramics are capable of inciting an adverse tissue reaction, which is orchestrated by cells of the monocyte/macrophage lineage. Three experimental approaches have been taken by our group to potentially mitigate the adverse biological sequela of particle disease. These include: 1) interfering with ongoing migration of monocyte/macrophages to the implant site by inhibiting the chemokine system 2) altering the functional activities of local macrophages by converting pro-inflammatory M1 macrophages to an anti-inflammatory pro-tissue healing M2 phenotype and 3) modulating the production and release of pro-inflammatory cytokines, chemokines and other potentially harmful factors by inhibiting the key transcription factor NFκB.


First, a murine model of systemic trafficking of remotely infused macrophages to locally infused clinically relevant wear particles was established. After preliminary in vitro studies in which a key macrophage chemokine, MCP-1 was identified, blocking of this chemokine ligand-receptor axis using antagonists and knockouts was undertaken. Second, in vitro and in vivo studies were performed to convert M1 pro-inflammatory macrophages (associated with wear particles ± endotoxin) to an M2 alternative phenotype by the infusion of the anti-inflammatory cytokine Interleukin-4 (IL-4). Third, in vitro studies were undertaken in which activated macrophages were exposed to an NFκB decoy oligodeoxynucleotide (ODN), which interferes with the production of pro-inflammatory mediators. The analytical techniques used included bioluminescence, microCT, immunohistochemical and immunofluorescent microscopy, histomorphometry, ELISA, rT-PCR and cell sorting.


Interference of the MCP-1-CCR2 ligand-receptor axis decreased systemic macrophage migration to the area of particle infusion, and subsequent osteolysis at the implant site. Local delivery of IL-4 promoted an alternative anti-inflammatory M2 macrophage phenotype (rather than a pro-inflammatory M1 phenotype), mitigating inflammation and osteolysis. Preliminary studies exposing activated macrophages to NFκB ODN decreased pro-inflammatory cytokine production.


Macrophage-induced inflammation and osteolysis due to wear byproducts limit the longevity of joint replacements. The interventions outlined above may be useful in preventing these events. For example, coatings that limit macrophage migration to the implant site or local delivery of biologics that alter macrophage phenotype might facilitate osseointegration and provide a more robust bone-implant interface initially. Early osteolysis with a salvageable joint replacement might be mitigated by local infusion of IL-4 or an NFκB ODN. These treatments are less invasive compared to surgical revision, and might prolong the lifetime of a joint replacement in humans.