Mechanisms of KE298, 2-acetylthiomethyl-3-(4-methylbenzoyl) propionic acid, to suppress abnormal synovial cell functions in patients with rheumatoid arthritis.

Abstract

OBJECTIVE:

2-Acetylthiomethyl-3-(4-methylbenzoyl) propionic acid, KE298, a derivative or propionic acid developed in Japan has been shown to be effective for suppressing disease activity of rheumatoid arthritis (RA) in clinical trials in Japan. It is thus a candidate as a new disease modifying antirheumatic drug (DMARD). We analyzed effects of KE298 on synovial fibroblast-like cells in patients with RA to obtain insight into the clinical application of this medication.

METHODS:

RA synovial fibroblast-like cells were co-cultured with KE298 at 10(-4)-10(-5) M in the presence or absence of tumor necrosis factor-alpha 2 ng/ml, and their subsequent proliferative responses and proinflammatory cytokine and matrix metalloproteinase (MMP) production at the mRNA and protein levels were measured. Effects of KE298 on MMP-1 gene transcription and AP-1 transcription factor expression of RA synovial cells were studied by chloramphenicol acetyltransferase assay and gel shift assay, respectively.

RESULTS:

KE298 inhibited proliferation of RA synovial cells, proinflammatory cytokine production, and MMP-1 production mainly by reducing their transcription via downmodulation of AP-1 transcription factor.

CONCLUSION:

KE298 inhibits aberrant synovial cell functions of patients with RA by downregulating gene transcription, suggesting clinical application and usefulness of this new DMARD.

• Authors: T Sakane, N Suzuki, Y Hirose, K Miura, S Wakisaka, H Nagafuchi, M Ichino, T Tomita, H Hashimoto, T Ochi, S Mihara
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 24 Issue 11 Pg. 2213-20 (Nov 1997) ISSN: 0315-162X [Print] Canada
• PMID: 9375886 (Publication Type: Journal Article)

Chemical References

• Antirheumatic Agents
• Interleukin-6
• Phenylpropionates
• RNA, Messenger
• Transcription Factor AP-1
• Tumor Necrosis Factor-alpha
• Collagenases
• Matrix Metalloproteinase 1
• esonarimod

Topics

• Antirheumatic Agents (pharmacology)
• Arthritis, Rheumatoid (drug therapy)
• Cell Division (drug effects)
• Cells, Cultured
• Collagenases (metabolism)
• Gene Expression
• Humans
• Interleukin-6 (metabolism)
• Matrix Metalloproteinase 1
• Phenylpropionates (pharmacology)
• Polymerase Chain Reaction
• RNA, Messenger (analysis)
• Synovial Membrane (drug effects, metabolism)
• Transcription Factor AP-1 (metabolism)
• Transcription, Genetic
• Tumor Necrosis Factor-alpha (pharmacology)