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

• Published in: International immunopharmacology 2012-05, Vol.13 (1), p.54-60
• Main Authors: Du, Fang, Lü, Liang-jing, Teng, Jia-lin, Shen, Nan, Ye, Ping, Bao, Chun-de
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - enzymology; Arthritis, Rheumatoid - pathology; Benzopyrans - administration & dosage; Benzopyrans - adverse effects; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Biological and medical sciences; Cartilage; Cell Migration Assays; Cell Movement - drug effects; Cells, Cultured; Disease-modifying antirheumatic drugs; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - immunology; Fibroblasts - pathology; Gene expression; Humans; Inflammatory joint diseases; Interleukin 1; Interstitial collagenase; Invasiveness; Joint diseases; Male; Matrix metalloproteinase; Matrix Metalloproteinase 1 - biosynthesis; Matrix Metalloproteinase 1 - blood; Matrix Metalloproteinase 3 - biosynthesis; Matrix Metalloproteinase 3 - blood; Matrix metalloproteinases; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Recruitment; Rheumatoid arthritis; Stromelysin 1; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Synovial Membrane - drug effects; Synovial Membrane - enzymology; Synovial Membrane - immunology; Synovial Membrane - pathology; synoviocytes; Tumor necrosis factor- alpha
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2012.03.003

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 4weeks with an oral dosage of 25mg once daily, and 50mg/day for the subsequent 20weeks with an oral dosage of 25mg twice daily), T-614 group 2 (T-614 with an oral dosage of 25mg twice daily), or the MTX group (MTX 10mg/week orally for the first 4weeks and 15mg/week for the subsequent 20weeks). Serum samples were obtained at 0 and 24weeks. Levels of MMP-1 and MMP-3 were decreased significantly after 24week treatment of T-614 group 2 or MTX group. In vitro, RA FLS were pretreated with different doses of T-614 and then stimulated with TNF-α, IL-1β or IL-17A, respectively. Protein and mRNA levels of MMP-1 and MMP-3 were further determined. MMP-1 production was significantly inhibited at 50μg/ml T-614 and MMP-3 production was significantly inhibited at 5μg/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. ► Levels of serum MMP-1 and MMP-3 were decreased after T-614 therapy in RA patients. ► In vitro, T-614 inhibited the invasiveness of FLS. ► T-614 decreased expression of MMP-1 and MMP-3 in FLS both in mRNA and protein levels.