T-614 alters the production of matrix metalloproteinases (MMP-1 and MMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro

Matrix metalloproteinases (MMPs) have a pivotal role in the destruction of cartilage in rheumatoid arthritis (RA) joint, which is mainly produced by fibroblast-like synoviocytes (FLS). T-614 is effective for patients with active RA, however the mechanism has not been clarified. We first focus on the MMPs level in RA patients after T-614 treatment, in vivo. Eighty-six RA patients were assigned into 3 treatment groups randomly: T-614 group 1(T-614 for the first 4 weeks with an oral dosage of 25 mg once daily, and 50 mg/day for the subsequent 20 weeks with an oral dosage of 25 mg twice daily), T-614 group 2 (T-614 with an oral dosage of 25 mg twice daily), or the MTX group (MTX 10 mg/week orally for the first 4 weeks and 15 mg/week for the subsequent 20 weeks). Serum samples were obtained at 0 and 24 weeks. Levels of MMP-1 and MMP-3 were decreased significantly after 24 week treatment of T-614 group 2 or MIX group. In vitro, RA FLS were pretreated with different doses of T-614 and then stimulated with TNF-alpha, IL-1 beta or IL-17A, respectively. Protein and mRNA levels of MMP-1 and MMP-3 were further determined. MMP-1 production was significantly inhibited at 50 mu g/ml T-614 and MMP-3 production was significantly inhibited at 5 mu g/ml or more T-614. The mRNA expression profile was in accordance with the protein production. Inhibition of invasiveness was also seen after T-614 treatment. These results suggest that T-614 inhibits the invasiveness through decreasing the MMP-1 and MMP-3 production. Crown Copyright (C) 2012 Published by Elsevier B.V. All rights reserved.