Affiliations: Medical Engineering Division and IRC in Biomedical Materials, Department of Engineering, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK
Note: [] Address for correspondence: Dr. Tina T. Chowdhury, Department of Engineering, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK. Tel.: +44 207 882 5368; Fax: +44 208 983 3052; E-mail: T.T.Chowdhury@qmul.ac.uk.
Abstract: .NO and PGE2 are inflammatory mediators derived from the inducible iNOS and COX enzymes and are potentially important pharmacological targets in OA. Both mechanical loading and IL-1β will influence the release of .NO and PGE2. Accordingly, the current study examines the effect of dynamic compression on .NO and PGE2 release by human chondrocytes cultured in agarose constructs in the presence and absence of selective iNOS and COX-2 inhibitors. The current data demonstrate that IL-1β induced nitrite and PGE2 release and inhibited [3H]-thymidine and 35SO4 incorporation. Inhibitor experiments indicate that 1400W and NS-398 either partially reversed or abolished IL-1β induced nitrite and PGE2 release. IL-1β induced inhibition of cell proliferation and proteoglycan synthesis was partially reversed with 1400W but was not influenced by NS-398. For the dynamic loading experiments, 1400W and NS-398 either reduced or abolished the compression-induced inhibition of .NO and PGE2 release in the presence of IL-1β. The IL-1β induced inhibition of cell proliferation was not influenced by 1400W or NS-398 whereas strain-induced stimulation of proteoglycan synthesis in the presence of IL-1β was enhanced by 1400W. The data obtained using human chondrocytes demonstrate that IL-1β induced .NO and PGE2 release via an iNOS-driven-COX-2 inter-dependent pathway. This response could be reversed by dynamic compression. These data indicate interactions exist between the NOS and COX pathways, a finding which will provide new insights in the development of pharmacological or biophysical treatments for cartilage disorders such as OA.
