Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
J Cell Mol Med. 2019 Jan;23(1):380-394. doi: 10.1111/jcmm.13942. Epub 2018 Oct 19.
Osteoporosis is the most common osteolytic disease characterized by excessive osteoclast formation and resultant bone loss, which afflicts millions of patients around the world. Madecassoside (MA), isolated from Centella asiatica, was reported to have anti-inflammatory and antioxidant activities, but its role in osteoporosis treatment has not yet been confirmed. In our study, MA was found to have an inhibitory effect on the RANKL-induced formation and function of OCs in a dose-dependent manner without cytotoxicity. These effects were attributed to its ability to suppress the activity of two transcription factors (NFATc1 and c-Fos) indispensable for osteoclast formation, followed by inhibition of the expression of bone resorption-related genes and proteins (Acp5/TRAcP, CTSK, ATP6V0D2/V-ATPase-d2, and integrin β3). Furthermore, we examined the underlying mechanisms and found that MA represses osteoclastogenesis by blocking Ca oscillations and the NF-κB and MAPK pathways. In addition, the therapeutic effect of MA on preventing bone loss in vivo was further confirmed in an ovariectomized mouse model. Therefore, considering its ability to inhibit RANKL-mediated osteoclastogenesis and the underlying mechanisms, MA might be a potential candidate for treating osteolytic bone diseases.
骨质疏松症是最常见的溶骨性疾病，其特征是破骨细胞过度形成和骨丢失，影响全球数百万患者。从积雪草中分离得到的积雪草苷（MA）具有抗炎和抗氧化作用，但它在骨质疏松症治疗中的作用尚未得到证实。在我们的研究中，发现 MA 以剂量依赖的方式抑制 RANKL 诱导的破骨细胞形成和功能，而没有细胞毒性。这些作用归因于其抑制两个转录因子（NFATc1 和 c-Fos）活性的能力，这两个转录因子对于破骨细胞形成是必不可少的，随后抑制与骨吸收相关的基因和蛋白质（Acp5/TRAcP、CTSK、ATP6V0D2/V-ATPase-d2 和整合素 β3）的表达。此外，我们研究了潜在的机制，发现 MA 通过阻断 Ca 振荡和 NF-κB 和 MAPK 途径来抑制破骨细胞生成。此外，在去卵巢小鼠模型中进一步证实了 MA 预防骨丢失的治疗效果。因此，鉴于其抑制 RANKL 介导的破骨细胞生成的能力及其潜在机制，MA 可能是治疗溶骨性骨疾病的潜在候选药物。
