Abstract
AIMS: Bone destruction is a pivotal pathological factor in the development of joint disability in rheumatoid arthritis (RA) patients, and there is a paucity of safe and effective drugs targeting bone destruction. Xuetong (Kadsura heteroclita Roxb), a traditional Tujia medicine with blood-activating and pain-relieving properties, has been used for the treatment of RA. Xuetongsu, as the primary anti-RA active component, has demonstrated inhibitory effects on joint inflammation and swelling in arthritic rats, as well as the potential to prevent bone destruction. However, the precise mechanisms by which these effects occur remain to be elucidated. This study aims to explore the potential action targets and mechanisms of Xuetongsu in RA-induced bone destruction. METHODS: RA bone destruction is closely related to the activation of the RANKL/RANK/NFATc1 pathway. In this study, databases such as TDD were used for KEGG and GO enrichment analyses to identify the potential targets of Xuetongsu in regulating the RANKL/RANK/NFATc1 pathway for anti-RA bone destruction. Molecular docking was employed to evaluate the binding affinity and interaction sites between Xuetongsu and RANKL. For in vitro experiments, a RANKL-induced osteoclastogenesis model using RAW264.7 cells was established to assess Xuetongsu's effects on osteoclastogenesis and bone resorption capacity. In vivo, a stable adjuvant-induced arthritis rat model was developed to investigate the anti-bone destruction effects of oral Xuetongsu and systematically explore its underlying mechanisms. RESULTS: Based on the findings from both in vitro and in vivo experimental models, it was revealed that Xuetongsu can directly target RANKL and inhibit the activation of the RANKL/RANK/NFATc1 pathway, thereby suppressing osteoclast-mediated bone resorption and preventing osteoclastogenesis. CONCLUSION: These findings indicate that Xuetongsu has been demonstrated to inhibit bone destruction by targeting the RANKL/RANK/NFATc1 pathway and could serve as a potential therapeutic agent for RA-associated bone destruction.