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Rheumatology Advance Access originally published online on October 14, 2009
Rheumatology 2009 48(12):1590-1594; doi:10.1093/rheumatology/kep316
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis

Lucie Oslejsková1, Mariam Grigorian2, Hana Hulejová1, Jirí Vencovsky1, Karel Pavelka1, Jörg Klingelhöfer2, Steffen Gay3, Michel Neidhart3, Hana Brabcová4, David Suchy4 and Ladislav Senolt1

1Department of Rheumatology of the First Faculty of Medicine, Institute of Rheumatology and Connective Tissue Research Laboratory, Charles University in Prague, Prague, Czech Republic, 2Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark, 3Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland and 4Department of Clinical Pharmacology, Teaching Hospital, Pilsen, Czech Republic.

Correspondence to: Ladislav Senolt, Institute of Rheumatology Connective Tissue Research Laboratory, Na Slupi 4, 12850 Prague 2, Czech Republic. E-mail: seno{at}revma.cz


  Abstract

Objectives. To evaluate the association between metastasis-inducing protein S100A4 and disease activity in patients with RA, and to demonstrate the effect of TNF-{alpha} blocking therapy on plasma levels of S100A4 in these patients.

Methods. Plasma levels of the S100A4 protein were analysed in 40 anti-TNF-{alpha} naive patients with active RA. Of the 40 patients, 25 were treated with adalimumab and monitored over time. The conformational form of S100A4 was analysed using size-exclusion gel chromatography. TNF-{alpha} mRNA expression and protein synthesis were analysed by RT–PCR and ELISA, respectively.

Results. Baseline levels of S100A4 were significantly correlated with disease activity in RA patients (r = 0.41; P < 0.01). After 12 weeks of treatment with adalimumab, there was an obvious shift in the conformations of S100A4 from the multimeric to the dimeric forms, whereas the total levels of the S100A4 protein remained unchanged. This suggests that the bioactive (multimer) S100A4 may decline in response to successful treatment with adalimumab. In addition, we showed significant up-regulation of TNF-{alpha} mRNA (P < 0.01), and protein release to the cell culture medium of monocytes stimulated with the S100A4 multimer compared with those treated with the dimer and to the unstimulated monocytes (P < 0.001).

Conclusions. This is the first study to show that the levels of the S100A4 protein are correlated with RA disease activity. Furthermore, only the bioactive form, but not the total amount of S100A4, decreases after successful TNF-{alpha} blocking therapy in patients with RA. These data support an important role for the S100A4 multimer in the pathogenesis of RA.

KEY WORDS: S100A4 protein, Rheumatoid arthritis, Inflammation, TNF-{alpha} inhibitor

Submitted 6 April 2009; revised version accepted 28 August 2009.
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