title: T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro.
abstract: 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 25mg once daily, and 50mg/day for the subsequent 20 weeks 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 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 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 50 μg/ml T-614 and MMP-3 production was significantly inhibited at 5 μg/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.
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 145 Shan Dong Middle Road, Shanghai, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.forename: Liang-jing
authors.initials: LJ
authors.lastname: Lü
authors.forename: Jia-lin
authors.initials: JL
authors.lastname: Teng
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.forename: Chun-de
authors.initials: CD
authors.lastname: Bao
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D001578:Benzopyrans / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000097:blood*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000097:blood*; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D013449:Sulfonamides; C077313:T 614; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1