Pedunculoside attenuates pathological phenotypes of fibroblast-like synoviocytes and protects against collagen-induced arthritis

Abstract

Objectives: The discovery of alternative and well-tolerated anti-arthritic drugs, especially from natural products, is becoming an area of active research. Pedunculoside (PE) is a novel triterpene saponin extracted from the dried bark of Ilex rotunda Thunb. Limited published papers have reported its pharmacological properties, including anti-inflammatory, anti-myocardial ischaemia, anti-liver injury, and hypocholesterolaemic activities. However, the effect of PE on rheumatoid arthritis (RA) remains unknown. Here, we investigated the anti-arthritic effect of PE in both in vitro and in vivo models.

Method: The inhibitory effects of PE on proliferation, migration, and production of inflammatory mediators in primary fibroblast-like synoviocytes (FLSs) were examined by a 5-ethynyl-2ʹ-deoxyuridine incorporation assay, wound-healing assay, and real-time polymerase chain reaction, respectively. Cellular signalling mechanisms were analysed by Western blot. The in vivo studies were performed using a collagen-induced arthritis (CIA) rat model. Multiple methods, including arthritis scoring, enzyme-linked immunoassay, radiography, and histopathological assessment, were used to evaluate the therapeutic effects of PE on CIA rats.

Results: The in vitro studies revealed that PE significantly inhibited proliferation and migration of FLSs. PE also decreased the production of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, and tumour necrosis factor-α (TNF-α). Western blot results suggested that PE suppressed TNF-α-stimulated activation of p38 and extracellular signal-regulated kinase. The in vivo studies showed that PE treatment significantly inhibited synovial inflammation and bone destruction in CIA rats.

Conclusion: These results demonstrate that PE exerts an inhibitory role in FLSs and CIA rats, and therefore may have therapeutic value for the treatment of RA.

Acknowledgements

This study was supported by the National Natural Science Foundation of China [grant numbers 31870895, 31171135], the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (TAPP). This study was also supported in part by the Australian National Health and Medical Research Council (NHMRC) [numbers 1107828, 1027932], University of Western Australia Research Collaboration Awards.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supporting information

Additional Supporting Information may be found in the online version of this article.

Supplementary Figure S1. PE treatment has no effect on the viability and apoptosis of arthritic FLS cells.

Supplementary Figure S2. PE treatment has little effect on TNF-α-stimulated activation of JNK and NF-κB.

Supplementary Table S1. Effects of PE on organ coefficients and biochemical parameters in rats with collagen-induced arthritis.

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