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-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-17, tumor necrosis factor-alpha (TNF alpha) 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 TNF alpha 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. (c) 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.