Anti-inflammatory and osteoprotective effects of Chikusetsusaponin Ⅳa on rheumatoid arthritis via the JAK/STAT signaling pathway

Rheumatoid arthritis (RA) is a common autoimmune disease, for which no economical and safe target drug treatment is available. Chikusetsusaponin Ⅳa (CS-IVa), an active compound in Panax japonicus C.A. Mey, has a good anti-inflammatory effect, but whether this compound can serve as a targeted drug for RA and the corresponding therapeutic mechanism remain unclear.To investigate the anti-inflammatory and bone-protecting effects of CS-IVa on RA and the possible corresponding mechanisms of action.Biomarkers and underlying pathological mechanisms were examined by performing a bioinformatics analysis of RA synovial gene expression data profiles, and the feasibility of CS-IVa treatment for RA was predicted using molecular docking and molecular dynamics simulation techniques. Histomorphological and molecular biology techniques were used to verify the feasibility and molecular mechanism of CS-IVa treatment for RA in vivo using a collagen-induced arthritis (CIA) model.CS-IVa alleviated symptoms and reduced the immune organ index, arthritis index, hind paw thickness, and number of swollen joints in the foot for CIA mice. Bioinformatics analysis suggested that interferon-gamma (IFN-γ), interleukin-1 β (IL-1β), and the Janus kinase/signal transduction and activator of transcription (JAK/STAT) pathway played important roles in the pathogenesis of RA. The results of molecular docking and molecular dynamics simulations showed that CS-IVa bound effectively to IFN-γ and IL-1β and that the combined pose has good stability and flexibility. The histomorphological results showed that CS-IVa reduced joint histopathology scores, OARSI scores, and TRAP-positive cell counts. Molecular biology analysis indicated that CS-IVa reduced the concentration of inflammatory factors in the peripheral serum of CIA mice and suppressed the mRNA expression of these factors in the spleen in a dose-dependent manner. The protein expression level of the JAK/STAT pathway was also inhibited by CS-IVa.The results of the current study demonstrate a novel inhibitory effect of CS-IVa on inflammation and bone destruction in CIA mice, and the mechanism may be related to the JAK/STAT signaling pathway, which provides new insights into the development of CS-IVa as a therapeutic agent for RA.