Regulation of gelatinases expression by cytokines, endotoxin, and pharmacological agents in the human osteoarthritic knee.

We examined the amount of gelatinases (matrix metalloproteinase-2 and -9 [MMP-2 and MMP-9] in a series of chondral, meniscal, and synovial cultures of early osteoarthritis (OA) after treatment with or without catabolic cytokines. These included interleukin-1alpha(IL-1alpha) and tumor necrosis factor-alpha(TNF-alpha), lipopolysaccharide (LPS), and pharmacological agents, including plasmin/serine proteinase antagonist aprotinin, protein synthesis inhibitor cycloheximide, and protein kinase C (PKC) inhibitors staurosporine, H7, and Go6976 for investigation of their effects on MMP-2 and -9 production in OA. Gelatin zymography revealed that IL-alpha, TNF-alpha, and LPS could elevate MMP-2 secretion in all tissue cultures and also increase MMP-9 production in all synovial and some meniscal cultures. In contrast, aprotinin, cycloheximide, staurosporine, H7, and Go6976 could suppress MMP-2 secretion in all tissue cultures and also decrease MMP-9 production in all synovial and some meniscal cultures. Our data indicate that catabolic cytokines and LPS may promote tissue destruction and disintegration of extracellular matrix in early OA. Agents that target on the PKC pathway, plasmin/serine proteinase or protein synthesis for MMP-2 and -9 in early OA may inhibit the production of MMPs. These findings might contribute to the design of more efficacious therapies.