Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice
Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice
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DOI：
10.1016/j.bcp.2010.04.014
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发表时间：
2010-08-01
影响因子：
5.8
通讯作者：
Woo, Je-Tae
中科院分区：
文献类型：
--
作者：
Lee, Ji-Won;Kobayashi, Yasuhiro;Woo, Je-Tae
破骨细胞是具有骨吸收功能的多核细胞，从单核/巨噬细胞系的造血祖细胞分化而来。破骨细胞的骨吸收被认为是治疗骨质疏松、类风湿性关节炎和牙周炎等侵蚀性骨病的潜在治疗靶点。在本研究中，我们发现泽泻醇-B是泽泻中的一种植物类固醇，在体外和体内都显示出抑制破骨细胞生成的作用。RT-PCR分析显示，泽泻醇-B不影响1α，25(OH)(2)D-3诱导的成骨细胞RANKL、OPG和M-CSF的mRNAs的表达，但在小鼠骨髓细胞和原代成骨细胞与10(-8)M1α，25(OH)(2)D-3共培养时，泽泻醇-B对破骨细胞的形成有明显的抑制作用。我们进一步研究了泽泻醇-B对破骨细胞前体细胞的直接影响。在培养早期加入泽泻醇-B可强烈抑制RANKL诱导的破骨细胞形成，提示泽泻醇-B作用于破骨细胞前体抑制RANKL/RANK信号转导。在RANK信号通路中，泽泻醇-B抑制RANKL诱导的骨髓巨噬细胞JNK的磷酸化，抑制RANKL诱导的NFATc1和c-Fos的表达。此外，泽泻醇-B抑制成熟破骨细胞的凹坑形成活性并干扰肌动蛋白环的形成。在2-亚甲基-19-Nor-(20S)-1α，25(OH)(2)D-3(2md)(1α，25(OH)(2)D-3的类似物)诱导的高钙小鼠模型中，泽泻醇-B通过抑制破骨细胞的生成而显著抑制2md诱导的高钙血症。综上所述，这些发现表明泽泻-B可能是一种潜在的新型治疗分子，通过靶向破骨细胞的分化及其功能来治疗骨病。皇冠版权所有(C)2010由爱思唯尔公司出版。保留所有权利。
Osteoclasts, bone-resorbing multinucleated cells, are differentiated from hemopoietic progenitors of the monocyte/macrophage lineage. Bone resorption by osteoclasts is considered a potential therapeutic target to the treatment of erosive bone diseases, including osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we found that alisol-B, a phyto-steroid from Alisma orientale Juzepczuk, exhibited inhibitory effects on osteoclastogenesis both in vitro and in vivo. Although RT-PCR analysis showed that alisol-B did not affect the 1 alpha,25(OH)(2)D-3-induced expressions of RANKL, OPG and M-CSF mRNAs in osteoblasts, addition of alisol-B to co-cultures of mouse bone marrow cells and primary osteoblasts with 10(-8) M 1 alpha,25(OH)(2)D-3 caused significant inhibition of osteoclastogenesis. We further examined the direct effects of alisol-B on osteoclast precursors. Alisol-B strongly inhibited RANKL-induced osteoclast formation when added during the early stage of cultures, suggesting that alisol-B acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, alisol-B inhibited the phosphorylation of JNK, which are upregulated in response to RANKL in bone marrow macrophages, alisol-B also inhibited RANKL-induced expression of NFATc1 and c-Fos, which are key transcription factors for osteoclastogenesis. In addition, alisol-B suppressed the pit-forming activity and disrupted the actin ring formation of mature osteoclasts. In a hypercalcemic mouse model induced by 2-methylene-19-nor-(20S)-1 alpha,25(OH)(2)D-3 (2MD), an analog of 1 alpha,25(OH)(2)D-3, administration of alisol-B significantly suppressed 2MD-induced hypercalcemia as resulting from the inhibition of osteoclastogenesis. Taken together, these findings suggest that alisol-B may be a potential novel therapeutic molecule for bone disorders by targeting the differentiation of osteoclasts as well as their functions. Crown Copyright (C) 2010 Published by Elsevier Inc. All rights reserved.