title: Inhibition of adenosine kinase attenuates interleukin-1- and lipopolysaccharide-induced alterations in articular cartilage metabolism.
abstract: OBJECTIVE
  To investigate the effect of adenosine kinase inhibition on interleukin (IL)-1beta- and lipopolysaccharide (LPS)-induced cartilage damage.
  
  
  METHODS
  Articular cartilage was obtained from the metacarpophalangeal joints of 10 young adult horses. Following a stabilization period, weighed cartilage explants were exposed to IL-1beta (10 ng/ml) or LPS (50 microg/ml) to induce cartilage degradation. To test the potential protective effects of adenosine, these explants were simultaneously exposed to adenosine (100 microM), the adenosine kinase inhibitor 5'iodotubercidin (ITU, 1 microM) or to both adenosine and ITU. After 72 h in culture, conditioned medium was collected for evaluation of glycosaminoglycan (GAG), nitric oxide (NO), prostaglandin E2 (PGE2) and matrix metalloproteinase (MMP)-3 release.
  
  
  RESULTS
  IL-1beta and LPS stimulated significant release of GAG, NO, PGE2 and MMP-3. Incubation with ITU significantly inhibited both IL-1beta- and LPS-induced GAG release, but did not alter MMP-3 production. Exposure to ITU also reduced IL-1beta-induced PGE2 release and LPS-induced NO production. Direct adenosine supplementation did not attenuate the effects of IL-1beta or LPS, and the addition of adenosine or ITU in the absence of IL-1beta 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.
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA.
authors.forename: Raina
authors.initials: R
authors.lastname: Petrov
authors.forename: Melinda H
authors.initials: MH
authors.lastname: MacDonald
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Tesch
authors.forename: Hilary P
authors.initials: HP
authors.lastname: Benton
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D017077:Culture Media, Conditioned; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000378:metabolism; D006736:Horses; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D046509:Tissue Culture Techniques / Q000379:methods; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D006025:Glycosaminoglycans; D007375:Interleukin-1; D008070:Lipopolysaccharides; C034214:5-iodotubercidin; D009569:Nitric Oxide; D000248:Adenosine Kinase; D019278:Matrix Metalloproteinase 3; D000241:Adenosine; D015232:Dinoprostone; D014372:Tubercidin