The Journal of Experimental Medicine
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The Journal of Experimental Medicine, Vol 138, 461-472, Copyright © 1973 by The Rockefeller University Press

ARTICLE

RELEASE OF CARTILAGE MUCOPOLYSACCHARIDE-DEGRADING NEUTRAL PROTEASE FROM HUMAN LEUKOCYTES

A. Oronsky 1, L. Ignarro 1, and R. Perper 1

1 From The Research Department, Pharmaceuticals Division, CIBA-Geigy Corporation, Ardsley, New York 10502

The granule fraction of human leukocytes contains neutral protease capable of degrading the noncollagenous protein mucopolysaccharide matrix of cartilage at neutral pH in physiological salt solution. Cartilage degradation was monitored by quantitating the release of 35S from labeled rabbit ear cartilage. Degradation of cartilage matrix occurs when intact viable human leukocytes are incubated with cartilage opsonized with aggregated human gamma globulin (AHGG). During a similar 4 h incubation period cells did not degrade uncoated cartilage or cartilage coated with nonaggregated gamma globulin. Cells remain viable during the enzyme release process as evidenced by the absence of a cytoplasmic enzyme marker (lactic dehydrogenase) in the supernatant and dye exclusion studies. The release of 35S from labeled cartilage by human leukocytes in the presence of cartilage coated with AHGG (nonphagocytic enzyme release) was compared with the cartilage degrading activity of the supernatant from the same number of cells preincubated with a suspension of AHGG (phagocytic enzyme release). Nonphagocytic enzyme release by 5 x 106 cells provoked two to four times more 35S and ß-glucuronidase (ß-G) release from cartilage than phagocytic enzyme release conditions. ß-glucuronidase was used as an indicator of the release of lysosomal granule enzymes.

By the use of selected pharmacological agents it was possible to dissociate the enzyme release process from intrinsic enzyme (neutral protease) activity. Neutral protease and ß-G release by human cells in the presence of AHGG-coated cartilage was inhibited by 10–5M colchicine, whereas the protease activity, but not the release process, was inhibited by 10–6M gold thiomalate and 10% human serum. It is suggested that the release of a cartilage degrading neutral protease by viable human cells when exposed to AHGG might be a relevant model for the study of cartilage destruction as it occurs in rheumatoid arthritis.

 Submitted on April 11, 1973


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