Liu Chunfang, Yang Yue, Sun Danni, Wang Chao, Wang Hui, Jia Shiwei, Liu Liang, Lin Na
1 Institute of Chinese Materia Medica , China Academy of Chinese Medical Sciences, Beijing, China .
2 Guangzhou Kanghe Pharmaceutical Limited Company , Guangzhou, China .
Rejuvenation Res. 2015 Dec;18(6):528-42. doi: 10.1089/rej.2015.1688. Epub 2015 Sep 29.
Anemone flaccida Fr. Schmidt is used in the clinical compound prescription for the treatment of rheumatoid arthritis (RA) in China and has the traditional use of draining dampness, diminishing swelling, and relieving pain. Total saponins (TS) are the characteristic components and also the main active ingredients of A. flaccida. Previous reports indicated that TS possess anti-inflammatory and immunoregulatory properties; however, the effects of TS on bone destruction of RA have not been evaluated. In this study, our data first showed the therapeutic effects of TS on severity of arthritis and arthritis progression in collagen-induced arthritis (CIA) rats. Then, by microfocal computed tomography (CT) quantification, TS significantly increased bone mineral density, bone volume fraction, and trabecular thickness and decreased trabecular separation of inflamed joints both at peri-articular and extra-articular locations. TS also diminished the level of the bone resorption marker CTX-I and simultaneously increased the bone formation marker osteocalcin in sera of CIA rats. Interestingly, TS prevented bone destruction by reducing the number of osteoclasts in inflamed joints, reducing the expression of receptor activator of nuclear factor-κF (RANK) ligand (RANKL) and RANK, increasing the expression of osteoprotegerin (OPG), at both mRNA and protein levels, and decreasing the ratio of RANKL to OPG in inflamed joints and sera of CIA rats. This was further confirmed in the co-culture system of human fibroblast-like synovial and peripheral blood mononuclear cells. In addition, TS inhibited the levels of pro-inflammatory cytokines implicated in bone resorption, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), IL-6, IL-17, and IL-23 in sera and joints. These findings offer convincing evidence that TS attenuate RA partially by preventing both focal bone destruction and systemic bone loss. This anti-erosive effect results in part from inhibiting osteoclastogenesis by regulating the RANKL/RANK/OPG signaling pathway. The suppression of systemic and local pro-osteoclastogenic cytokines by TS was also highly effective.
威灵仙在中国临床复方中用于治疗类风湿关节炎（RA），传统上有祛湿、消肿、止痛的功效。总皂苷（TS）是威灵仙的特征性成分，也是其主要活性成分。既往报道表明TS具有抗炎和免疫调节特性；然而，TS对RA骨破坏的影响尚未评估。在本研究中，我们的数据首次显示了TS对胶原诱导性关节炎（CIA）大鼠关节炎严重程度和关节炎进展的治疗作用。然后，通过微焦点计算机断层扫描（CT）定量分析，TS显著增加了关节周围和关节外炎症关节的骨矿物质密度、骨体积分数和小梁厚度，并减少了小梁间距。TS还降低了CIA大鼠血清中骨吸收标志物CTX-I的水平，同时增加了骨形成标志物骨钙素的水平。有趣的是，TS通过减少炎症关节中破骨细胞的数量、降低核因子κF受体激活剂（RANK）配体（RANKL）和RANK的表达、增加骨保护素（OPG）在mRNA和蛋白质水平的表达，以及降低CIA大鼠炎症关节和血清中RANKL与OPG的比值，从而预防骨破坏。这在人成纤维细胞样滑膜细胞和外周血单核细胞的共培养系统中得到了进一步证实。此外，TS抑制了血清和关节中与骨吸收相关的促炎细胞因子水平，如白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNFα）、IL-6、IL-17和IL-23。这些发现提供了令人信服的证据，表明TS通过预防局部骨破坏和全身骨质流失来部分减轻RA。这种抗侵蚀作用部分是通过调节RANKL/RANK/OPG信号通路抑制破骨细胞生成而实现的。TS对全身和局部促破骨细胞生成细胞因子的抑制也非常有效。
