Bacopaside I Ameliorates Collagen‐Induced Arthritis in Rats and the Pathogenic Behaviors of Fibroblast‐Like Synoviocytes via Wnt/β‐Catenin Pathway Suppression

Fibroblast-like synoviocytes (FLS) drive rheumatoid arthritis (RA) progression. Bacopaside I (BSI), a major component of the anti-RA herb Bacopa monnieri , demonstrates anti-arthritic effects in RA animal models; however, its precise anti-rheumatic mechanisms, especially regarding suppression of RA-FLS pathogenicity, remain unclear. Collagen-induced arthritis (CIA) rats and TNF-α-stimulated RA-FLS were used as in vivo and in vitro models of RA. We studied BSI's therapeutic potential in CIA rats and its influences on TNF-α-induced migration, invasion, and inflammation in RA-FLS, focusing on the underlying mechanism of Wnt/β-catenin pathway inhibition. BSI exhibited arthritis-alleviating activity in CIA rats, as evidenced by reductions in paw swelling, arthritis index, and histological damage to ankle joints. It also decreased serum and synovial levels of IL-1β, IL-6, and TNF-α, indicating anti-inflammatory effects in vivo. At non-cytotoxic concentrations, BSI inhibited migration, invasion, and F-actin remodeling in TNF-α-stimulated RA-FLS. Similar to its anti-inflammatory activity in vivo, BSI decreased pro-inflammatory factor production in vitro, including IL-1β, IL-6, IL-8, MMP-2, and MMP-9. Mechanistically, BSI treatment inhibited Wnt/β-catenin pathway activation in both CIA rat synovium and TNF-α-stimulated RA-FLS, as demonstrated by decreased Wnt1, p-GSK-3β (Ser9), and β-catenin protein levels, increased p-β-catenin, reduced β-catenin nuclear translocation, and a lower TOP/FOP ratio. Importantly, the critical involvement of this pathway was further confirmed by the loss of BSI's benefits following β-catenin overexpression in TNF-α-stimulated RA-FLS. BSI ameliorates arthritis severity and RA-FLS pathogenicity by suppressing the Wnt/β-catenin pathway, highlighting its promise as a novel candidate for RA treatment.