[Mechanistic study on alleviation of bone erosion in CIA mice by Scutellariae Radix-Gardeniae Fructus drug pair via regulation of SphK1-mediated glycolysis].

This study aims to investigate whether Scutellariae Radix-Gardeniae Fructus(S-G) drug pairs alleviate joint inflammation and bone erosion in collagen-induced arthritis(CIA) mice by regulating sphingosine kinase 1(SphK1)-mediated glycolysis and inhibiting the differentiation of osteoclasts(OCs) induced by receptor activator of nuclear factor-κB ligand(RANKL). Potential therapeutic targets of S-G drug pairs were screened via network pharmacology, followed by Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment and molecular docking analyses. The effects of S-G drug pairs on bone erosion, inflammatory cytokines, glycolysis-related factors, and OCs differentiation were evaluated using both the CIA mouse model and the RAW264.7 cell in vitro induction system. In vivo results showed that S-G drug pairs alleviated joint swelling and synovial inflammation, reduced OCs number, and modulated the expression of key cytokines, including RANKL, osteoprotegerin(OPG), interleukin(IL)-6, and IL-10. In vitro findings further demonstrated that serum containing the drug significantly inhibited RANKL-induced OCs differentiation, reduced F-actin ring formation, and lowered levels of lactate acid(LA) and lactate dehydrogenase A(LDH-A). Additionally, it suppressed the expression of glycolysis-and bone resorption-related proteins and genes such as SphK1, pyruvate kinase M2(PKM2), oncoprotein c-Myc(c-Myc), and cathepsin K(CTSK), while also weakening the interaction between SphK1 and PKM2. In conclusion, S-G drug pairs could inhibit OCs differentiation by regulating SphK1-mediated glycolytic metabolism, thereby mitigating rheumatoid arthritis-induced bone erosion.