Nitric oxide inhibits aggrecan degradation in explant cultures of equine articular cartilage.
Arthroses are debilitating diseases of articular joints which result in erosion of the cartilage extracellular matrix. Nitric oxide (NO) is a major component of the inflammatory response, and has been implicated as a mediator of some of the effects of the proinflammatory cytokine, interleukin-1 (IL-1). In this study, we investigated the role of NO in the regulation of proteoglycan degradation in equine articular cartilage. NO fully mediated the suppressive effect of IL-1 on proteoglycan synthesis. However, NO was also antagonistic to proteoglycan degradation, irrespective of whether degradation was initiated by 10 ng/ml IL-1 or 1 micromol/l all-trans retinoic acid (RA) which (unlike IL-1) does not elevate NO production. This was confirmed using the NO donor 2,2'-(hydroxynitrosohydrazono) bis-ethanamine (DETA-NONOate) and the iNOS inhibitor L-N5-iminoethyl ornithine (dihydrochloride) (L-NIO). The G1 fragments of aggrecan were detected in the media and extracts of cartilage explant cultures treated with all-trans RA, DETA-NONOate and L-NIO. The presence of exogenous NO in culture resulted in a decrease in the appearance of the 'aggrecanase' cleavage epitope. Therefore, changes in the appearance of the G1 fragment expressing the 'aggrecanase' cleavage epitope in the media emulated the glycosaminoglycan loss from the tissue. These results lend further support to the hypothesis that NO has an anticatabolic role in equine cartilage proteoglycan degradation, and suggest that this may be mediated by the regulation of 'aggrecanase' activity. Therefore, any pharmacological intervention using NO as a target must take into account both its catabolic and anticatabolic roles in joint tissue turnover.
Bird
J L
JL
Department of Farm Animal and Equine Medicine and Surgery, Royal Veterinary College, North Mymms, Hatfield, Herts, UK.
May
S
S
Bayliss
M T
MT
D053674:Aggrecans; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D016326:Extracellular Matrix Proteins; D006736:Horses / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type; D008970:Molecular Weight; D009569:Nitric Oxide / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism*
D053674:Aggrecans; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D011509:Proteoglycans; D009569:Nitric Oxide