Inhibition of adenosine kinase attenuates interleukin-1-and lipopolysaccharide-induced alterations in articular cartilage metabolism

Objective: To investigate the effect of adenosine kinase inhibition on interleukin (IL)-1 beta- and lipopolysaccharide (LPS)-induced cartilage damage. Design: Articular cartilage was obtained from the metacarpophalangeal joints of 10 young adult horses. Following a stabilization period, weighed cartilage explants were exposed to IL-1 beta (10 ng/ml) or LPS (50 mu g/ml) to induce cartilage degradation. To test the potential protective effects of adenosine, these explants were simultaneously exposed to adenosine (100 mu M), the adenosine kinase inhibitor 5'iodotubercidin (ITU, 1 mu M) or to both adenosine and ITU. After 72 h in culture, conditioned medium was collected for evaluation of glycosaminoglycan (GAG), nitric oxide (NO), prostaglandin E-2 (PGE(2)) and matrix metalloproteinase (MMP)-3 release. Results: IL-1 beta and LIPS stimulated significant release of GAG, NO, PGE(2) and MMP-3. Incubation with ITU significantly inhibited both IL-1 beta- and LPS-induced GAG release, but did not alter MMP-3 production. Exposure to ITU also reduced IL-1 beta-induced PGE2 release and LPS-induced NO production. Direct adenosine supplementation did not attenuate the effects of IL-1 beta or LPS, and the addition of adenosine or ITU in the absence of IL-1 beta or LPS did not have any detectable effect on cartilage metabolism in this model. Conclusions: The adenosine kinase inhibitor ITU attenuated experimentally induced cartilage damage in an in vitro cartilage explant model. Release of adenosine from chondrocytes may play a role in the cellular response to tissue damage in arthritic conditions and modulation of these pathways in the joint may have potential for treatment of arthropathies. (c) 2005 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.