Stimulation of macrophage TNFα production by orthopaedic wear particles requires activation of the ERK1/2/Egr‐1 and NF‐κB pathways but is independent of p38 and JNK

Abstract

Bone loss that causes aseptic loosening of orthopaedic implants is initiated by pro-inflammatory cytokines produced by macrophages in response to implant-derived wear particles. MAPK and NF-κB signaling pathways are activated by the particles; however, it is not clear which of the signaling pathways are important for the initial response to the wear particles and which are only involved at later steps in the process, such as osteoclast differentiation. Here, we show that the ERK1/2, p38, JNK, and NF-κB pathways are rapidly activated by the wear particles but that only the ERK1/2 and NF-κB pathways are required for the initial response to the wear particles, which include increases in TNFα promoter activity, TNFα mRNA expression, and secretion of TNFα protein. Moreover, ERK1/2 activation by wear particles is also required for increased expression of the transcription factor Egr-1 as well as Egr-1's ability to bind to and activate the TNFα romoter. These results, together with our previous studies of the PI3K/Akt pathway, demonstrate that wear particles coordinately activate multiple signaling pathways and multiple transcription factors to stimulate production of pro-inflammatory cytokines, such as TNFα. The current study also demonstrates that the signaling pathways are activated to a much greater extent by wear particles with adherent endotoxin than by "endotoxin-free" wear particles. These results, together with those demonstrating the requirement for ERK1/2/Egr-1 and NF-κB, show that activation of these signaling pathways is responsible for the ability of adherent endotoxin to potentiate cytokine production, osteoclast differentiation, and bone loss induced by wear particles.

Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways

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Activation of Egr-1 in Human Lung Epithelial Cells Exposed to Silica through MAPKs Signaling Pathways

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Biology of implant wear

“…25 It has been shown that adherent endotoxin substantially enhances the effects of wear particles on pro-inflammatory cytokine production, osteoclast differentiation and osteolysis through stimulation of MAPK and NF-κB activation induced by wear particles. 26 After release, wear particles may be coated by different molecules (e.g. lipids, carbohydrates, proteins) and this coating may then evoke a reaction of the innate or acquired immune system.…”