IMPAIRED ACTIVITY OF PROTEASE INHIBITORS TOWARDS NEUTROPHIL ELASTASE BOUND TO HUMAN ARTICULAR-CARTILAGE

Objective-To investigate the effects of protease inhibitors on the abi lity of free and cartilage bound neutrophil elastase to degrade cartil age proteoglycan in vitro. Methods-Cryostat sections of human articula r cartilage were used as substrate, and proteoglycan loss induced by f ree or cartilage bound elastase was quantified by alcian blue staining , followed by scanning and integrating microdensitometry. Results-High molecular mass protease inhibitors (alpha(1) protease inhibitor, alph a(2) macroglobulin, and soya bean trypsin inhibitor) and synovial flui d from patients with rheumatoid arthritis were effective in blocking p roteoglycan loss from sections treated with free elastase, but their a ctivity towards cartilage bound elastase was much reduced. In contrast , low molecular mass elastase inhibitors (N-methoxysuccinyl-Ala-Ala-Pr o-Val chloromethylketone and ONO-5046 (N-[2-[4-(2,2-dimethylpropionylo xy) phenylsulphonylamino]benzoyl] amino-acetic acid) were effective ag ainst free and cartilage bound elastase. Conclusion-The binding of ela stase to cartilage appears to be a mechanism whereby the enzyme can re main active in the presence of high molecular mass protease inhibitors .