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.
Highlights
Rheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease mainly affecting the joints, characterized by synovial hyperplasia and inflammatory cell infiltration, leading to tissue destruction and functional disability [1,2]
These results suggest that non-toxic concentrations of celastrol ranging from 0.05 mM to 0.2 mM could inhibit RA-fibroblast-like synoviocytes (FLSs) migration and invasion induced by LPS in vitro
Several studies have shown that celastrol has antiarthritic activities in an adjuvant-induced arthritis (AIA) model [19,31], the precise mechanisms by which celastrol can alleviate the clinical symptoms of experimental arthritic models are not well defined
Summary
Rheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease mainly affecting the joints, characterized by synovial hyperplasia and inflammatory cell infiltration, leading to tissue destruction and functional disability [1,2]. Novel biologic agents that target tumor necrosis factor or interleukin (IL)-1 and IL-6, in addition to T- and B-cell inhibitors, have resulted in favorable clinical outcomes in patients with RA [3]. Among the inflammatory cell populations that might participate in RA pathogenesis, FLSs are crucial in initiating and driving RA in concert with inflammatory cells. They contribute to the destruction of cartilage and bone by secreting metalloproteinases (MMPs) into the synovial fluid and by direct invasion into extracellular matrix (ECM), further exacerbating joint damage [4,5]. The control of RA-FLS invasion represents an important therapeutic target
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