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Lorenz, Wolfgang; Buhrmann, Constanze; Mobasheri, Ali; Lueders, Cora und Shakibaei, Mehdi: Bacterial lipopolysaccharides form procollag-enendotoxin complexes that trigger cartilage inflammation and degeneration: implications for the development of rheumatoid arthritis. In: Arthritis Research & Therapy 2013, 15:R111


Introduction: We have previously reported that bacterial toxins, especially endotoxins such as lipopolysaccharides (LPS), might be important causative agents in the pathogenesis of rheumatoid arthritis (RA) in an in vitro model that simulates the potential effects of residing in damp buildings. Since numerous inflammatory processes are linked with the nuclear factor-kappa B (NF-kappa B), we investigated in detail the effects of LPS on the NF-kappa B pathway and the postulated formation of procollagen-endotoxin complexes. Methods: An in vitro model of human chondrocytes was used to investigate LPS-mediated inflammatory signaling. Results: Immunoelectron microscopy revealed that LPS physically interact with collagen type II in the extracellular matrix (ECM) and anti-collagen type II significantly reduced this interaction. BMS-345541 (a specific inhibitor of I kappa B kinase (IKK)) or wortmannin (a specific inhibitor of phosphatidylinositol 3-kinase (PI-3K)) inhibited the LPS-induced degradation of the ECM and apoptosis in chondrocytes. This effect was completely inhibited by combining BMS345541 and wortmannin. Furthermore, BMS-345541 and/or wortmannin suppressed the LPS-induced upregulation of catabolic enzymes that mediate ECM degradation (matrix metalloproteinases-9, -13), cyclooxygenase-2 and apoptosis (activated caspase-3). These proteins are regulated by NF-kappa B, suggesting that the NF-kappa B and PI-3K pathways are involved in LPS-induced cartilage degradation. The induction of NF-kappa B correlated with activation of I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation and p65 nuclear translocation. Further upstream, LPS induced the expression of Toll-like receptor 4 (TLR4) and bound with TLR4, indicating that LPS acts through TLR4. Conclusion: These results suggest that molecular associations between LPS/TLR4/collagen type II in chondrocytes upregulate the NF-kappa B and PI-3K signaling pathways and activate proinflammatory activity.