Destruction of articular cartilage by alpha2macroglobulin elastase complexes: role in rheumatoid arthritis

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Abstract
OBJECTIVE Neutrophil elastase accounts for the ability of some fresh rheumatoid synovial fluids to degrade cartilage matrix in vitro. The aim of this study was to determine if enzyme activity could result from depletion of synovial fluid inhibitors or protection of the enzyme from inhibition. METHODS The ability of synovial fluids to inhibit porcine pancreatic elastase was investigated together with chemical pretreatments capable of inactivating alpha1 protease inhibitor (α1PI) or preventing formation of alpha2 macroglobulin (α2M) elastase complexes. Subsequently, complexes of human neutrophil elastase with α2M were prepared and applied to frozen sections of cartilage. Proteoglycan loss was quantified by alcian blue staining and scanning and integrating microdensitometry. Parallel studies were carried out using a low molecular weight chromogenic elastase substrate. The effects of α1PI and SF on these systems were investigated. Finally, synovial fluids were subjected to gel filtration and the fractions assayed for elastase activity. High molecular weight fractions were pooled, concentrated, and tested for their ability to degrade cartilage sections. RESULTS All synovial fluids reduced the activity of porcine pancreatic elastase, the inhibition mainly being attributable to α1PI, whereas remaining activity resulted from complexes of elastase with α2M. Complexes of human neutrophil elastase with α2M were shown to cause proteoglycan degradation in frozen sections of human articular cartilage. Alpha1PI prevented α2M elastase complexes from degrading cartilage but not the chromogenic substrate. The data suggested that α1PI does not inhibit elastase bound to α2M but sterically hinders the complex. However, only one of five synovial fluids was able to completely block the actions of α2M elastase complexes against cartilage. Gel filtration of rheumatoid synovial fluids showed elastase and cartilage degrading activity to be associated with fractions that contained α2M, and not with fractions expected to contain free enzyme. CONCLUSIONS The data suggest that synovial fluid α2M elastase complexes can degrade cartilage matrix in rheumatoid arthritis.

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