Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis.
OBJECTIVE
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) alpha 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.
Catrina
A I
AI
Department of Rheumatology, Karolinska Hospital, Stockholm, Sweden.
Lampa
J
J
Ernestam
S
S
af Klint
E
E
Bratt
J
J
Klareskog
L
L
Ulfgren
A-K
AK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000503:physiopathology / Q000628:therapy*; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood*; D019278:Matrix Metalloproteinase 3 / Q000097:blood*; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D016896:Treatment Outcome
D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D019715:Tissue Inhibitor of Metalloproteinase-1; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D000068800:Etanercept