Abstract
In the pathogenesis of rheumatoid arthritis (RA), rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) have tumor-like characteristics, mainly manifested by hyperproliferation and resistance to apoptosis and then it will erode the bone and cartilage, eventually leading to joint destruction. Paris saponin VII (PS VII) is an active compound derived from a traditional herbal medicine named Trillium tschonoskii Maxim, which has anti-tumor, analgesic, and immunomodulatory effects. However, its anti-RA effect has not yet been reported. This study was to investigate the effect of PS VII on two rheumatoid arthritis fibroblast-like synoviocytes lines (RA-FLS and MH7A) and adjuvant-induced arthritis (AIA) in rats. In vitro, the effects of PS VII on the proliferation, cell cycle, and apoptosis of RA-FLS and MH7A cells were detected by MTT, flow cytometry, and western blot analysis. In vivo, the effect of PS VII on the weight of the rat, paw swelling, ankle joint diameter, arthritis index, serum inflammatory cytokines (TNF-α, IL-6, and IL-1β), histopathological assessment and apoptosis proteins in the synovial tissues were evaluated in AIA rats. The in vitro studies showed that PS VII inhibited the proliferation of RA-FLS and MH7A cells, induced S phase arrest and triggered cell apoptosis mainly through the mitochondrial apoptotic pathway and the regulation of JNK and p38 MAPK pathways. The in vivo studies revealed that PS VII could improve ameliorate body weight, paw swelling, ankle joint diameter, reduce the spleen and thymus index, suppress the production of TNF-α, IL-6 and IL-1β, improve histopathological changes and regulate the expressions of apoptosis proteins in AIA Rats. In conclusion, PS VII could inhibit the proliferation and trigger apoptosis of RA-FLS and MH7A cells by regulating the mitochondrial apoptosis pathway and the JNK and p38 MAPK pathways, and alleviate the symptoms of RA, signifying it to be one of the potential anti-RA therapeutics.
Highlights
Rheumatoid arthritis is a wide spread autoimmune disease with a high incidence and causes significant disability to those it affects (Petrovská et al, 2021)
We investigated the therapeutic effect of Paris saponin VII (PS VII) on rheumatoid arthritis fibroblast-like synoviocytes and adjuvantinduced arthritis (AIA) rats
To evaluate the cytotoxicity of PS VII in rheumatoid arthritis (RA)-FLS and MH7A cells, the cell viability was measured after treatment with multiple concentrations of PS VII for 24, 48, 72 h (Figure 1)
Summary
Rheumatoid arthritis is a wide spread autoimmune disease with a high incidence and causes significant disability to those it affects (Petrovská et al, 2021). It is commonly recognized that the pathogenesis of RA involves the infiltration of interstitial inflammatory cells, the tumor-like proliferation of synovial cells, pannus formation, the erosion of bones and articular cartilage (Josef et al, 2018). Numerous studies have shown that the RA-FLS from RA patients with the characteristics similar to tumor cells, undergoing the tumor-like proliferation, prolonging the cell growth cycle and resisting apoptotic ability, were the main incentives of synovial hyperplasia (Nygaard and Firestein, 2020). The RA-FLS from patients had resistance to apoptosis due to the imbalance of anti-apoptotic and pro-apoptotic molecules. The current clinical treatment strategies use non-steroidal antiinflammatorydrugs (NSAIDs), disease-modifying antirheumatic drugs (DMARD), glucocorticoids, and biological agents to improve clinical symptoms, but accompanied by related adverse reactions, such as gastrointestinal bleeding risk, liver and kidney toxicity, infection, and tumor risk (Wang et al, 2018; Conigliaro et al, 2019). It is urgent to develop new drugs to inhibit the proliferation and induce apoptosis of RA-FLS, which is one of the critical strategies for the treatment of RA
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