Endogenous Activation of Latent Collagenase by Rheumatoid Synovial Cells

Abstract

To elucidate the mechanism of synovial damage in rheumatoid arthritis, we studied the activation of latent collagenases released from adherent rheumatoid synovial cells in culture. Latent enzyme was not complexed with alpha2 macroglobulin, the prinicpal proteinase inhibitor in serum, and could be activated by trypsin in the presence of alpha2 macroglobulin if sufficient proteinase was added to saturate inhibitor. Latent collagenase bound half as effectively to collagen fibrils as active enzyme. Plasmin was a threefold better activator of latent enzyme than trypsin and could be generated by addition of plasminogen to synovial-cell cultures. Production of both collagenase and plasminogen activator was inhibited by dexamethasone (10(-9) M). These studies emphasize in importance of control of activation in regulation collagenase activity, It is likely that rheumatoid synovium produces both latent collagenase and plasminogen activator; plasmin is activated from its zymogen, plasminogen, present in inflamed tissues, and in turn activates collagenase.

Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (‘gelatinase’) by human neutrophil elastase and cathepsin G

“…It has been reported that the zymogens of collagenase and MMP-3 are activated either by direct limited proteolysis by endopeptidases including trypsin, ~-chymotrypsin, plasma kallikrein, plasmin, thermolysin and cathepsin B [12][13][14]18,19], or, alternatively, by mercurial compounds such as NH2PhHgAc that may cause certain conformational changes in the molecule [12][13][14]. The present study has shown for the first time that proMMP-3 can be activated with elastase and cathepsin G from human neutrophils.…”

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

“…This may well be a component of the plasminogen activator (PA)/plasmin cascade, since plasmin is inhibited by ␣ 1 PI and is a known activator of procollagenases (18)(19)(20)(21). These observations suggest that a furin-dependent activation mechanism occurs early in the cartilage assay, while a serine proteinase pathway, possibly the PA/plasmin cascade, is important later in the cartilage assay.…”

“…The precise mechanisms of activation of procollagenases in cartilage are not fully understood. The serine proteinase plasmin is a known activator of several proMMPs, including proMMP-1 (collagenase 1), proMMP-13 (collagenase 3), and proMMP-3 (stromelysin 1) (18)(19)(20)(21). MMP-3 itself can activate other proMMPs, including proMMP-1, proMMP-8 (collagenase 2), proMMP-9 (gelatinase B), and proMMP-13 (22)(23)(24)(25).…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…We have shown that both furin-and trypsin-like serine proteinases are involved in the cascades that lead to such activation (148,176), although the precise proteinases involved remain unknown. It has long been established that plasmin can activate procollagenases (36), leading to the suggestion that the PA/plasmin cascade might function in various resorbing tissues to activate proMMPs, including procollagenases (37). A role for this cascade in the activation of endogenous cartilage metalloproteinases was subsequently reported (181,182), and there is also evidence for its presence in invasive rheumatoid synovium (183).…”

“…The reasons for such conflicting observations are unknown, but the differences may be partly attributable to the different pathologies reported in the models used (32). Furthermore, plasmin has contrasting roles in the context of arthritis: plasmin-mediated fibrinolysis is important in maintaining a healthy joint, while plasmin can also contribute directly to ECM proteolysis by cleaving matrix components (glycoproteins, fibronectin, and proteoglycans) or indirectly by proMMP activation and subsequent ECM degradation (36)(37)(38)(39). Other arthritis-relevant roles for plasmin include intracellular signaling via activation of PAR-1 in association with integrin ␣9␤1 (40), activation of growth factors such as transforming growth factor ␤ (TGF␤) (41,42), release of IGF-1 from IGFBPs (43), and activation of the complement cascade (35).…”