Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920–1181, Japan.
Biol Pharm Bull. 2012;35(10):1765-74. doi: 10.1248/bpb.b12-00445.
One of the mediators of osteoclast differentiation is receptor activator of nuclear factor κB ligand (RANKL), which is produced by osteoblasts. Binding of RANKL to its receptor, RANK, activates several signaling pathways, including those involving mitogen-activated protein kinases (MAPKs), nuclear factor κB (NF-κB), nuclear factor of activated T cells c1 (NFATc1) and Ca(2+)-calcineurin. In the present study, we found that tetrandrine, a bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra S. MOORE, significantly ameliorated the decrease of bone mass in sciatic-neurectomized osteoporosis model mice. It appears that tetrandrine acts directly on osteoclast precursors, since tetrandrine inhibited osteoclast differentiation not only in mouse bone marrow cells, but also in monocultures of murine macrophage RAW 264.7 cells without osteoblasts. Tetrandrine suppressed RANKL-induced amplification of NFATc1, a master regulator of osteoclast differentiation. However, it did not affect other signaling molecules such as MAPKs and NF-κB. These results suggest that tetrandrine is a candidate for the treatment of bone-destructive diseases, or at least a suitable lead compound for further development.
破骨细胞分化的介质之一是核因子 κB 配体受体激活剂（RANKL），它由成骨细胞产生。RANKL 与其受体 RANK 的结合激活了几个信号通路，包括丝裂原活化蛋白激酶（MAPK）、核因子 κB（NF-κB）、激活 T 细胞核因子 1（NFATc1）和 Ca(2+)-钙调神经磷酸酶。在本研究中，我们发现从粉防己（Stephania tetrandra S. MOORE）的根中提取的双苄基异喹啉生物碱汉防己甲素可显著改善坐骨神经切断骨质疏松症模型小鼠的骨量减少。汉防己甲素似乎直接作用于破骨细胞前体，因为汉防己甲素不仅在小鼠骨髓细胞中，而且在没有成骨细胞的单核培养的鼠巨噬细胞 RAW 264.7 细胞中也抑制破骨细胞分化。汉防己甲素抑制了 RANKL 诱导的 NFATc1 的扩增，NFATc1 是破骨细胞分化的主要调节因子。然而，它不影响其他信号分子，如 MAPK 和 NF-κB。这些结果表明汉防己甲素是治疗骨破坏性疾病的候选药物，或者至少是进一步开发的合适先导化合物。
