Destruction of articular cartilage by alpha2 macroglobulin elastase complexes: role in rheumatoid arthritis

doi:10.1136/ard.58.2.109

Annals of the Rheumatic Diseases 1999;58:109-113; doi:10.1136/ard.58.2.109

Ann Rheum Dis 1999;58:109-113 ( February )

Extended reports

Destruction of articular cartilage by alpha₂ macroglobulin elastase complexes: role in rheumatoid arthritis Adrian R Moore, Andrew Appelboam, Kazuhito Kawabata, José A P Da Silva, David D'Cruz, Gerald Gowland, Derek A Willoughby

Department of Experimental Pathology, St Bartholomew's and Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ

Correspondence to: Dr Moore.

Accepted for publication 28 October 1998

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 couldresult from depletion of synovial fluid inhibitors or protectionof the enzyme frominhibition.
METHODS $---$ The ability of synovial fluids to inhibit porcine pancreatic elastase was investigated together with chemical pretreatmentscapable of inactivating alpha₁ protease inhibitor ( $alpha$ ₁PI) or preventingformation of alpha₂ macroglobulin ( $alpha$ ₂M) elastase complexes. Subsequently,complexes of human neutrophil elastase with $alpha$ ₂M were preparedand applied to frozen sections of cartilage. Proteoglycan losswas quantified by alcian blue staining and scanning and integratingmicrodensitometry. Parallel studies were carried out using a lowmolecular weight chromogenic elastase substrate. The effects of $alpha$ ₁PI and SF on these systems were investigated. Finally, synovialfluids were subjected to gel filtration and the fractions assayedfor elastase activity. High molecular weight fractions were pooled,concentrated, and tested for their ability to degrade cartilagesections.
RESULTS $---$ All synovial fluids reduced the activity of porcine pancreatic elastase, the inhibition mainly being attributable to $alpha$ ₁PI,whereas remaining activity resulted from complexes of elastasewith $alpha$ ₂M. Complexes of human neutrophil elastase with $alpha$ ₂M wereshown to cause proteoglycan degradation in frozen sections ofhuman articular cartilage. Alpha₁PI prevented $alpha$ ₂M elastase complexesfrom degrading cartilage but not the chromogenic substrate. Thedata suggested that $alpha$ ₁PI does not inhibit elastase bound to $alpha$ ₂Mbut sterically hinders the complex. However, only one of fivesynovial fluids was able to completely block the actions of $alpha$ ₂Melastase complexes against cartilage. Gel filtration of rheumatoidsynovial fluids showed elastase and cartilage degrading activityto be associated with fractions that contained $alpha$ ₂M, and not withfractions expected to contain freeenzyme.
CONCLUSIONS $---$ The data suggest that synovial fluid $alpha$ ₂M elastase complexes can degrade cartilage matrix in rheumatoidarthritis.

Keywords: alpha₁ antitrypsin; alpha₂ macroglobulin; glycosaminoglycans; neutrophil elastase; proteoglycans; synovial fluid

CiteULike

Complore

Connotea

Del.icio.us Add to Digg

Digg

Technorati What's this?

This article has been cited by other articles:

Tchetverikov, I, Lohmander, L S, Verzijl, N, Huizinga, T W J, TeKoppele, J M, Hanemaaijer, R, DeGroot, J (2005). MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis. Ann Rheum Dis 64: 694-698 [Abstract] [Full Text]
Chan, S. C. H., Shum, D. K. Y., Ip, M. S. M. (2003). Sputum Sol Neutrophil Elastase Activity in Bronchiectasis: Differential Modulation by Syndecan-1. Am. J. Respir. Crit. Care Med. 168: 192-198 [Abstract] [Full Text]
MASI, A T, ALDAG, J C, MALAMET, R L, HUTCHINSON, D, MOOTS, R (2001). Heavy cigarette smoking and RA. Ann Rheum Dis 60: 1154-1155 [Full Text]
Busso, N., Dudler, J., Salvi, R., Peclat, V., Lenain, V., Marcovina, S., Darioli, R., Nicod, P., So, A. K., Mooser, V. (2001). Plasma Apolipoprotein(a) Co-Deposits with Fibrin in Inflammatory Arthritic Joints. Am. J. Pathol. 159: 1445-1453 [Abstract] [Full Text]

Services

Citing Articles

Google Scholar

PubMed

Topic Collections

Bookmark with

What's this?

Register for free content

The full back archive is now available for all BMJ Journals. Institutional subscribers may access the entire archive as part of their subscription. Personal subscribers will also have access to all content when logged in. Non-subscribers who register have free access to all articles published before 2006 right back to volume 1 issue 1. Register here to access the free archive of all BMJ Journals.

Don't forget to sign up for content alerts so you keep up to date with all the articles as they are published.