Background: Rheumatoid arthritis (RA) is a systemic disease characterized by chronic synovial infiltration and proliferation, cartilage destruction, and joint injury. Ginkgolide B (GB) is an extract of the leaves of Ginkgo biloba, and pharmacological studies have shown that it has anti-inflammatory and anti-apoptotic activities. The purpose of this study was to investigate the anti-RA properties of GB.
Methods: In vivo, we established a collagen II-induced arthritis (CIA) mouse model. Mice were divided into five groups (n=10): sham, CIA, GB (10 µM), GB (20 µM), and GB (40 µM). We measured arthritis score, synovial histopathological change, and peripheral blood cytokine levels. In vitro, we used lipopolysaccharide (LPS)-induced-fibroblast-like synoviocytes (RA-FLSs) as the study subject. Cell viability, apoptosis, and inflammatory cytokines levels were detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, flow cytometry, and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), respectively. Finally, the protein expression of wingless-type family member 5A (Wnt5a), c-Jun N-terminal kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 were detected by Western blot.
Results: Arthritis scores, synovial hyperplasia, and cartilage and bone destruction were significantly ameliorated by GB. Additionally, GB decreased the serum levels of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α), matrix metalloproteinase (MMP)-3 and MMP-13, and increased IL-10. In vitro, we found that GB remarkably inhibited RA-FLSs viability at 24 or 48 h in a concentration-dependent manner. The apoptotic ratio was reduced by GB, and it increased the expression of cleaved-Caspase-3 and Bax while decreasing Bcl-2 expression in RA-FLSs. Furthermore, GB attenuated the progression of inflammation by mediating inflammatory cytokine release and MMPs gene expression. Meanwhile, GB inactivated the expression levels of Wnt5a, phosphorylated (p)-JNK, and p-P65 in the synovial tissues and RA-FLSs.
Conclusions: This study was the first to demonstrate that the anti-RA effect of GB is related to reducing articular cartilage and bone destruction, inducing RA-FLSs apoptosis, and regulating inflammatory cytokine release and the Wnt5a/JNK/NF-κB axis. All the findings highlight that GB might provide a novel treatment approach for RA.
Keywords: Ginkgolide B (GB); fibroblast-like synoviocytes (FLSs); inflammation; rheumatoid arthritis (RA).
2020 Annals of Translational Medicine. All rights reserved.