Pathobiochemical Significance of Granulocyte Elastase Complexed with Proteinase Inhibitors: Effect on Glycosaminoglycan Metabolism in Cultured Synovial Cells

Abstract

Summary:Interactions between elastase Inhibitor complexes and synovial cells are of special interest, since, in chronic joint diseases, granulocytes release large amounts of elastase into the synovial fluid and connective tissue, where the proteinase is böund to cti-proteinase inhibitor and a 2 -macroglobulin. To study the effect of elastase-a 2 -macroglobulin and elastase-a r proteinase inhibitor complexes on the glycosaminoglycan metabolism of cultured synovial cells, we determined the distribution of [ 3 H]glucosamine-labelled hyaluronate, which represents the main synthesized glycosaminoglycan, and of 35 SO4~-labelled chondroitin sulphate into the intracellular, pericellular and extracellular compartments of the cell culture. Exposure of the synovial cells to elastase-a 2 -inacroglobulin complexes leads to an enhanced synthesis and secretion of hyaluronate and chondroitin sulphate, and also induces a rise of the fibronectin concentration in the medium. Analogous but less pronounced effects are observed in the presence of elastase-a r proteinase inhibitor complexes. Native uncomplexed elastase, however, causes no significant changes in hyaluronate metabolism. An increase of prostaglandin E 2 in the culture medium during incubation with elastase inhibitor complexes occurs in parallel to the stimulatory effect on glycosaminoglycan metabolism. Our results demonstrate that elastase, whose enzymic activity is inactivated by the formation of complexes with fy -proteinase inhibitor or a 2 -macroglobulin, nevertheless acts äs an inflammatory mediator, which in vitro induces metabolic changes closely resembling the in vivo findings in inflammatory joint diseases.