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Anti-tumour necrosis factor (TNF)- therapy (etanercept) down-regulates

serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis

A. I. Catrina, J. Lampa, S. Ernestam1, E. af Klint, J. Bratt1, L.

Klareskog and A.-K. Ulfgren

Department of Rheumatology, Karolinska Hospital and Department of

Rheumatology, Huddinge Hospital, Stockholm, Sweden

Objectives. Matrix metalloproteinases (MMPs) are cytokine-modulated

enzymes that play an important role in the pathogenesis of rheumatoid

arthritis (RA) by inducing bone resorption and cartilage destruction.

This study evaluated the modulation of serum and synovial MMPs and their

inhibitor, tissue inhibitor of matrix metalloproteinases (TIMP)-1, by

therapy with soluble tumour necrosis factor (TNF) receptor

(etanercept).

Methods. Serum samples were collected from 60 RA patients at baseline

and after 8 or 12 weeks of treatment. Paired synovial biopsies were

obtained from 11 patients at two time points, before and after 8 weeks

of treatment. We measured serum levels of MMP-1, MMP-3 and TIMP-1 by

ELISA. Immunohistological analysis of synovial tissue was performed

using monoclonal antibodies specific for MMP-1, MMP-3 and TIMP-1.

Results. Etanercept therapy significantly down-regulated serum levels

of MMP-3 and MMP-1 in parallel with the reduction in inflammatory

parameters (C-reactive protein concentration and erythrocyte

sedimentation rate) in RA patients.

Baseline pretreatment serum levels of MMP-3 correlated with changes in

clinical disease activity during therapy. No consistent changes in serum

level of TIMP-1 were observed, while ratios of MMP-1 and MMP-3 to TIMP-1

were down-regulated following etanercept treatment. Immunohistochemical

analyses revealed great interindividual variability, with generally a

high level of expression of MMP and low expression of TIMP. No

significant change in the pattern or number of positive cells occurred

during therapy.

Conclusions. In RA patients, etanercept therapy down-regulates serum

levels of MMP-3 and MMP-1 and the ratio between MMPs and TIMP-1. This

may be an important mechanism for the prevention of future development

of joint damage.