Abstract
Invasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway play a critical role in RA-FLS invasion induced by lipopolysaccharide (LPS). The present study aimed to explore the anti-invasive activity of celastrol on LPS-stimulated human RA-FLSs, and to elucidate the mechanism involved. We investigated the effect of celastrol on LPS-induced FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Results showed that celastrol suppressed LPS-stimulated FLS migration and invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppressing the binding activity of NF-κB in the MMP-9 promoter, and suppressed the TLR4/MyD88/NF-κB pathway. Administration of celastrol (0.5 mg/kg and 1 mg/kg, intraperitoneally) daily for 3 weeks in a collagen-induced arthritis rat model markedly alleviated the clinical signs, synovial hyperplasia and inflammatory cell infiltration of joints. In conclusion, celastrol might inhibit FLS migration and invasion induced by LPS by suppressing TLR4/NF-κB-mediated MMP-9 expression, providing a theoretical foundation for the clinical treatment of RA with celastrol.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / genetics
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Arthritis, Experimental / pathology
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Arthritis, Rheumatoid / drug therapy
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Arthritis, Rheumatoid / genetics
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Arthritis, Rheumatoid / pathology
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Cell Cycle / drug effects
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Cell Movement / drug effects
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Cell Survival / drug effects
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Collagen Type II
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Female
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Gene Expression Regulation / drug effects*
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Humans
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Joint Capsule / drug effects*
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Joint Capsule / metabolism
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Joint Capsule / pathology
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Lipopolysaccharides / pharmacology
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Pentacyclic Triterpenes
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Primary Cell Culture
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Rats
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Rats, Wistar
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Signal Transduction
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism
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Triterpenes / pharmacology*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Collagen Type II
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Lipopolysaccharides
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NF-kappa B
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Pentacyclic Triterpenes
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Tlr4 protein, rat
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Toll-Like Receptor 4
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Triterpenes
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Matrix Metalloproteinase 9
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celastrol
Grants and funding
This study was supported by grants from National Natural Science Foundation of China (no. 81173603), and Postgraduate Research and Innovation Project of Jiangsu Province (no. CXZZ11-0998). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.