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Open Access Research article

The active form of MMP-3 is a marker of synovial inflammation and cartilage turnover in inflammatory joint diseases

Shu Sun1*, Anne-Christine Bay-Jensen1, Morten A Karsdal1, Anne Sofie Siebuhr1, Qinlong Zheng2, Walter P Maksymowych34, Thorbjørn G Christiansen5 and Kim Henriksen1

Author Affiliations

1 Nordic Bioscience Biomarkers and Research, Herlev, Denmark

2 Nordic Bioscience Biomarkers and Research, Beijing, China

3 University of Alberta, Edmonton, Canada

4 Alberta Innovates-Health Solutions, Alberta, Canada

5 Orthopaedic Surgical Unit, Gentofte University Hospital, Hellerup, Denmark

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BMC Musculoskeletal Disorders 2014, 15:93  doi:10.1186/1471-2474-15-93

Published: 19 March 2014

Abstract

Background

Matrix metalloproteinase-3 (MMP-3) plays an important role in the pathology of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Measurement of active MMP-3 in clinical samples could provide information about progression of rheumatoid diseases, and potentially response to treatment. Hence, we aimed to develop a sensitive assay specifically measuring the active form of MMP-3 (act-MMP-3) both in ex vivo models and in human sera.

Methods

A monoclonal antibody against the first 6 amino acids of act-MMP-3 was developed, and the specificity was carefully tested by comparing total and active MMP-3. A technically robust act-MMP-3 ELISA was produced. For biological validation, human synovial membrane and human cartilage explant (HEX) culture models were measured and compared by ELISA and immunoblots. For clinical relevance, the serum levels of act-MMP-3 in AS and RA patients before and after anti-TNF-α treatment were evaluated.

Results

A highly specific and technically robust ELISA detecting act-MMP-3 in serum was developed. The lower limit of detection was 33.7 pg/mL. The dilution and spiking recovery of human serum was within 100 ± 20%. The average intra- and inter-assay variations were 3.1% and 13.5% respectively.

High levels of act-MMP-3 expression were observed in human synovial membrane culture and oncostatin M and TNF-α stimulated human cartilage. In a cross-sectional study of both AS and RA patients, serum act-MMP-3 level was correlated with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). In addition, in patients receiving anti-TNF-α treatment, the serum level of act-MMP-3 was significantly reduced compared to baseline level reflecting the anti-inflammatory effects of the treatment.

Conclusion

We have successfully developed an assay measuring act-MMP-3 in human serum showing correlation to inflammatory markers. Further studies are required to clarify, whether act-MMP-3 can serve as a predictive marker for outcome in chronic rheumatoid disorders.

Keywords:
MMP-3; Active form; Ankylosing spondylitis; Rheumatoid arthritis; Serum