کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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3381489 | 1220258 | 2006 | 11 صفحه PDF | دانلود رایگان |
SummaryObjectivePeroxynitrite (ONOO−) is formed in the inflamed and degenerating human joint. Peroxynitrite-modified collagen-II (PMC-II) was recently discovered in the serum of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Therefore we investigated the cellular effects of PMC-II on human mesenchymal progenitor cells (MPCs) as a model of cartilage and cartilage repair cells in the inflamed and degenerating joint.DesignMPCs were isolated from the trabecular bone of patients undergoing reconstructive surgery and were differentiated into a chondrogenic lineage. Cells were exposed to PMC-II and levels of the proinflammatory mediators nitric oxide (NO) and prostaglandin E2 (PGE2) measured. Levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), phosphorylated mitogen activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) activation were measured by enzyme linked immunosorbent assay (ELISA) together with specific MAPK and NF-κB inhibitors.ResultsPMC-II induced NO and PGE2 synthesis through upregulation of iNOS and COX-2 proteins. PMC-II also lead to the phosphorylation of MAPKs, extracellularly regulated kinase 1/2 (ERK1/2) and p38 [but not c-Jun NH2-terminal kinase (JNK1/2)] and the activation of proinflammatory transcription factor NF-κB. Inhibitors of p38, ERK1/2 and NF-κB prevented PMC-II induced NO and PGE2 synthesis, iNOS and COX-2 protein expression and NF-κB activation.ConclusioniNOS, COX-2, NF-κB and MAPK are known to be activated in the joints of patients with OA and RA. PMC-II induced iNOS and COX-2 synthesis through p38, ERK1/2 and NF-κB dependent pathways suggesting a previously unidentified pathway for the synthesis of the proinflammatory mediators, NO and PGE2, further suggesting that inhibitors of these pathways may be therapeutic in the inflamed and degenerating human joint.
Journal: Osteoarthritis and Cartilage - Volume 14, Issue 5, May 2006, Pages 460–470