Endogenously produced adenosine regulates articular cartilage matrix homeostasis: enzymatic depletion of adenosine stimulates matrix degradation.
OBJECTIVE
Enhanced extracellular levels of adenosine have been shown to inhibit experimentally induced cartilage degradation. The objective of this study was to investigate the role of adenosine and A(2)adenosine receptors in regulating cartilage homeostasis in the absence of inflammatory stimuli.


METHODS
Cartilage explants were exposed to adenosine deaminase (ADA) to deplete extracellular adenosine, and conditioned medium was collected for evaluation of glycosaminoglycan (GAG), prostaglandin E(2)(PGE(2)), nitric oxide (NO), and matrix metalloproteinases-3 and -13 (MMP-3, MMP-13) levels. In a second set of experiments, cartilage incubated with ADA was simultaneously exposed to the adenosine kinase inhibitor 5'-iodotubercidin (ITU) to inhibit adenosine breakdown, or to the A(2A)adenosine receptor agonist N(6)-[2-(3,5-dimethoxyphenyl)-ethyl]adenosine (DPMA). Finally, explants were incubated with the adenosine receptor antagonists ZM241385, CGS15943, theophylline or caffeine to block normal receptor activation by endogenous adenosine.


RESULTS
Exposure to ADA induced a concentration-dependent increase in GAG release and production of total MMP-3, MMP-13, PGE(2), and NO. Both ITU and DPMA inhibited the ADA-mediated increases in GAG release and PGE(2), and NO production, but only ITU inhibited MMP-13 release. Exposure to ZM 241385 increased GAG, MMP-3 and MMP-13 release. Additionally, CGS 15943 increased MMP-3 production while theophylline increased GAG, PGE(2), and NO release.


CONCLUSIONS
Endogenous adenosine levels appear to regulate cartilage matrix homeostasis even in the absence of inflammation. Regulation occurs, at least in part, through activation of cell surface receptors. This study suggests that autocrine and paracrine responses to adenosine release are important for maintenance of healthy articular cartilage.
Tesch
A M
AM
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA.
MacDonald
M H
MH
Kollias-Baker
C
C
Benton
H P
HP
D000241:Adenosine / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D019902:Chondrocytes / Q000502:physiology*; D006706:Homeostasis; D006736:Horses
D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase; D000241:Adenosine