Bacterial lipopolysaccharides form procollagen-endotoxin complexes that trigger cartilage inflammation and degeneration: implications for the development of rheumatoid arthritis
1 Institute of Indoor Diagnostics, Marconistrasse 23, D-40589 Duesseldorf, Germany
2 Musculoskeletal Research Group, Institute of Anatomy, Ludwig Maximilian University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany
3 Medical Research Council-Arthritis Research UK Centre for Musculoskeletal Ageing Research, Arthritis Research UK Pain Centre, Arthritis Research UK Centre for Sport, Exercise, and Osteoarthritis, Faculty of Medicine and Health Sciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, LE12 5RD, Nottingham, United Kingdom
4 Center of Excellence in Genomic Medicine Research (CEGMR), King AbdulAziz University, Jeddah 21589, Kingdom of Saudi Arabia
5 Schools of Pharmacy and Life Sciences, University of Bradford, Richmond Road, Bradford, BD7 1DP, United Kingdom
6 German Heart Institute Berlin, Department of Thoracic and Cardiovascular Surgery, Laboratory for Tissue Engineering, Augustenburger Platz 1, 13353 Berlin, Germany
Arthritis Research & Therapy 2013, 15:R111 doi:10.1186/ar4291Published: 10 September 2013
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-κB (NF-κB), we investigated in detail the effects of LPS on the NF-κB pathway and the postulated formation of procollagen-endotoxin complexes.
An in vitro model of human chondrocytes was used to investigate LPS-mediated inflammatory signaling.
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 IκB 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 BMS-345541 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-κB, suggesting that the NF-κB and PI-3K pathways are involved in LPS-induced cartilage degradation. The induction of NF-κB correlated with activation of IκBα kinase, IκBα phosphorylation, IκBα 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.
These results suggest that molecular associations between LPS/TLR4/collagen type II in chondrocytes upregulate the NF-κB and PI-3K signaling pathways and activate proinflammatory activity.