Differential release of plasminogen activator and latent collagenase from mononuclear cell-stimulated synovial cells

Independent studies have previously shown that mononuclear cell supernatants stimulate the release of plasminogen activator and latent collagenase from synovial cell monolayer cultures. Simultaneous secretion of these enzymes could be an important pathway for tissue destruction under inflammatory conditions, since plasminogen activator can cause activation of latent collagenase in the presence of plasminogen. We investigated the kinetics of release of the two enzymes from synovial cells in response to the addition of mononuclear cell supernatants and retinoic acid. Synovial cells derived from osteoarthritic and rheumatoid arthritic patients responded similarly. Plasminogen activator is released within a few hours of stimulation, and secretion usually stops when the stimulus is removed. In contrast, significant amounts of collagenase are secreted only after an initial lag period of 1--2 days, and secretion is sustained long after removal of mononuclear cell supernatant. Another difference in regulation of the secretion of these two neutral proteinases is that the addition of all-trans retinoic acid to the same synovial cell culture elevates plasminogen activator secretion while suppressing that of latent collagenase. Differential regulation of these enzymes under conditions of chronic inflammation may allow for continual accumulation of latent enzyme(s) which are activated during short periods of plasminogen activator release.