Degradation in vivo of articular cartilage in rheumatoid arthritis by leucocyte elastase from polymorphonuclear leucocytes

Abstract

Using a specific substrate, no leucocyte elastase activity could be detected in 55 synovial fluids, including 29 from patients with rheumatoid arthritis (RA). However, a high percentage of samples contained phagocytic inclusions of elastase, alpha 1-proteinase inhibitor (alpha 1-PI) and alpha 2-macroglobulin (alpha 2-MG) in both the polymorphonuclear (PMN) and mononuclear phagocytes. Immunofluorescence and indirect peroxidase-antiperoxidase staining of articular cartilage (ACA) from 52% of 21 patients with RA and one with juvenile RA (JRA) showed presence of elastase in the superficial layer of microscopically intact but proteoglycan depleted pannus-free ACA. In histologically altered pannus-free RA-ACA superficial elastase deposits were found in 24% of the cases. Adjacent ACA sections contained IgG, C3, alpha 1-PI and rarely alpha 2-MG. RA-ACA below or surrounded by pannus showed close contact with intact and decaying PMN in 62% and 48% of the cases, respectively. ACA specimens from patients with degenerative disease and systemic lupus were negative. These findings strongly suggest that PMN leucocyte elastase is operative in the degradation of RA-ACA and JRA-ACA, and that this activity is largely dependent upon the presence of entrapped immune complexes in such cartilage.

Plasma Levels of Inhibitor-Bound Leukocytic Elastase in Rheumatoid Arthritis Patients

“…, (b) these PMN leukocytes release elastase (3) as well as a number of other enzymes and inflammatory mediators (4) during phagocytosis or other mechanisms (5), (c) substantial quantities of elastase have been identified in the synovium (6,7) or, complexed to naturally occuring inhibitors in synovial fluids of RA patients (8)(9)(10)(11)(12) or penetrated into the articular cartilage (13,14).…”

Neutrophil-mediated cartilage injury in vitro is enhanced by tumour necrosis factor alpha

“…This effect of TNFe was retained when the neutrophils were preincubated with TNFc~ and washed before incubating with the cartilage, indicating that TNFe increased the release from neutrophils of substances which degrade cartilage matrix. Degradation of cartilage proteoglycan has been largely attributed to neutrophil proteolytic enzymes, particularly elastase [1,3,4,[7][8][9][10]. TNF~ increases neutrophil respiratory burst and granule enzyme release [16,21,22].…”

“…This damage has been mainly attributed to neutrophil proteolytic enzymes, particularly leucocyte elastase [1,3,4,[7][8][9][10] and also to products of the neutrophil respiratory burst [11,12].…”

“…Neutrophils predominate during acute inflammatory episodes of rheumatoid arthritis [1,2] and contribute to the articular cartilage damage which is a feature of this disease [3,4].…”

Stimulation of Human Neutrophil Degranulation by Mefloquine

“…Neutrophils are found in in creased numbers in the joint fluid and synovial tissues [29,30] during acute stages of the disease and at the cartilage-pannus border in chronically inflamed joints [31][32][33]. These neutrophils have been implicated in the degradation and impaired metabolism of carti lage in rheumatoid arthritis through the release of lysosomal enzymes and oxygen-reactive species [17,[34][35][36][37][38][39][40], Mefloquine which inhibits a number of neutrophil functions (superoxide release resulting from NADPH oxidase activity and the neutrophil iodination reac tion) may be useful as an adjunct to existing therapy.…”