千根草中伪愈创木内酯6-OAP靶向c-Src抑制RA骨破坏的分子机制研究

抑制破骨细胞过度活化是治疗类风湿关节炎骨破坏的重要策略之一。传统中药千根草具有消炎祛湿的功效，申请人前期发现千根草活性成分伪愈创木内酯6-OAP抑制RANKL诱导的NF-κB与NFATc1的转录活性，进一步研究发现6-OAP抑制破骨细胞生成和骨吸收功能以及破骨细胞相关基因的表达。分子对接提示c-Src可能是6-OAP的潜在靶点。在此基础上，体内外模型进一步评价6-OAP抑制破骨细胞生成，发挥骨保护作用的效果，通过探索RANKL诱导的破骨细胞生成的NF-κB、PLCγ、NFATc1等信号通路，揭示6-OAP抑制破骨细胞生成可能的分子机制，同时聚焦6-OAP潜在的分子标靶c-Src，进一步明确c-Src是否为6-OAP的直接靶标。研究将有助于深入理解中药千根草活性成分6-OAP通过抑制破骨细胞发挥治疗RA骨破坏的机制，为中医药防治RA机制研究提供思路。

Targeting excessive activation of osteoclasts is one of the effective therapeutic strategies for the treatment of rheumatoid arthritis (RA) bone destruction. The traditional Chinese medicine Euphorbia thymifolia Linn has anti-inflammatory and dampness-removing effects. We found that pseudoguaianolide 6-OAP from Euphorbia thymifolia Linn not only significantly suppresses the transcriptional activities of NF-κB and NFATc1, but also inhibits RANKL-induced osteoclastogenesis, bone resorption and the expression of osteoclast-related genes induced by RANKL. Molecular docking revealed that c-Src may be a potential direct target for 6-OAP. Accordingly, the effects of 6-OAP on inhibition of osteoclastogenesis and its osteo-protective property are evaluated both in vitro and in vivo. The signaling pathways of osteoclastogenesis including NF-κB, PLCγ, NFATc1 are explored to find the possible molecular mechanism of 6-OAP on RANKL induced osteoclastogenesis with a special focus on whether c-Src is a direct target of 6-OAP. The purpose of this research is to illustrate the mechanism of pseudoguaianolide 6-OAP, the active ingredient of Euphorbia thymifolia Linn, against RA bone destruction via inhibiting osteoclastogenesis, which provide novel strategy on the traditional Chinese medicine for the treatment of RA.