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
- 23 July 2008
- journal article
- research article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 217 (3), 652-666
- https://doi.org/10.1002/jcp.21539
Abstract
Bone loss that causes aseptic loosening of orthopedic 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 promoter. 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. J. Cell. Physiol. 217: 652–666, 2008.This publication has 93 references indexed in Scilit:
- The selectivity of protein kinase inhibitors: a further updateBiochemical Journal, 2007
- Response of monocytes exposed to phagocytosable particles and discs of comparable surface roughnessBiomaterials, 2007
- Toll‐like receptors in the interface membrane around loosening total hip replacement implantsJournal of Biomedical Materials Research Part A, 2007
- Comparison of the roles of IL-1, IL-6, and TNFα in cell culture and murine models of aseptic looseningBone, 2006
- Endogenous Protein Kinase Inhibitor γ Terminates Immediate-early Gene Expression Induced by cAMP-dependent Protein Kinase (PKA) SignalingPublished by Elsevier BV ,2005
- c-Jun NH2-Terminal Kinase Inhibitor Anthra(1,9-cd)pyrazol-6(2H)-one Reduces Inducible Nitric-Oxide Synthase Expression by Destabilizing mRNA in Activated MacrophagesMolecular Pharmacology, 2003
- Microphthalmia Transcription Factor Is a Target of the p38 MAPK Pathway in Response to Receptor Activator of NF-κB Ligand SignalingPublished by Elsevier BV ,2002
- Specificity and mechanism of action of some commonly used protein kinase inhibitorsBiochemical Journal, 2000
- Requirement for NF-κB in osteoclast and B-cell developmentGenes & Development, 1997
- Endotoxin detectionImmunology Today, 1992