Mechanism of proteoglycan aggregate degradation in cartilage stimulated with oncostatin M.
OBJECTIVE
To investigate the potential synergistic and differential effects of cytokine combinations on proteoglycan aggregate catabolism in cartilage.


METHODS
Bovine articular cartilage explants were maintained in organ culture and subjected to stimulation with cytokine combinations including interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, IL-17, tumor necrosis factor-alpha (TNFalpha) and oncostatin M (OSM). Aggrecan, link protein and hyaluronan (HA) release and degradation were analyzed, and the effect of the hyaluronidase inhibitor apigenin was investigated.


RESULTS
For all cytokine mixtures studied cleavage of aggrecan only by aggrecanase action was apparent. However, OSM acting synergistically with IL-1 or TNFalpha produced a rapid release of all proteoglycan aggregate components due to both aggrecan and HA degradation. This was abolished by the hyaluronidase inhibitor, apigenin. In addition, in the presence of OSM a low molecular weight aggrecan G3 product was observed, suggesting altered aggrecanase cleavage activity is induced by this cytokine.


CONCLUSIONS
Under cytokine stimulation, aggrecan release from cartilage may take place via proteolysis of the aggrecan core protein or via depolymerization of HA, with the latter mechanism being induced by OSM. OSM is associated with joint inflammation and its participation may account for the more rapid loss of aggrecan from articular cartilage in the inflammatory arthritides, compared to osteoarthritis.
Durigova
M
M
Shriners Hospital for Children, Department of Surgery, McGill University, Montreal, Quebec, Canada.
Roughley
P J
PJ
Mort
J S
JS
D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D047310:Apigenin / Q000494:pharmacology; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D016207:Cytokines / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology*; D053683:Oncostatin M / Q000494:pharmacology*; D011509:Proteoglycans / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099249:Proteoglycan Link Protein
D053674:Aggrecans; D047310:Apigenin; D016207:Cytokines; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D006820:Hyaluronic Acid; D007378:Interleukins; D053683:Oncostatin M; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; D000099249:Proteoglycan Link Protein