Synthesis and biological evaluation of rhein amides as inhibitors of osteoclast differentiation and bone resorption
Synthesis and biological evaluation of rhein amides as inhibitors of osteoclast differentiation and bone resorption
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大黄酸酰胺类破骨细胞分化和骨吸收抑制剂的合成及生物学评价
DOI：
10.1016/j.ejmech.2016.08.004
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发表时间：
2016-11-10
影响因子：
6.7
通讯作者：
Deng, Lianfu
中科院分区：
文献类型：
--
作者：
Xu, Xing;Qi, Xueyu;Deng, Lianfu
针对破骨细胞过度活化和分化的方法被认为是骨质疏松症或骨质减少的有效治疗选择。本论文合成了一系列大黄酸衍生物，并分别采用MTF法和TRAP法进行了它们对骨髓源性巨噬细胞（BMSCs）的细胞毒性筛选和体外破骨细胞活化和分化的抑制作用。两种大黄酸衍生物d 6和d11对Bcl 3的活化和分化抑制率分别为98%和85%，对Bcl 3无细胞毒性。随后，进一步验证最有效的化合物d 6对TRAP阳性多核细胞形成和骨吸收的抑制作用，如通过TRAP染色和骨吸收测定所评价的。破骨细胞标志物基因测定的d 6的调节揭示了用M-CSF和RANK 1处理Bcirrhosis，结果表明，d 6可刺激与破骨细胞活化和分化密切相关的NFATc 1、c-fos、TRAP、MMP-9和组织蛋白酶K的mRNA表达，而d 6可降低这些基因的mRNA表达。提示d 6可能通过RANKL/RANK/NFATc 1途径调节破骨细胞活性。因此，我们目前的工作有望提供一个非常有前途的方法，开发一种新型的抗骨质疏松剂。(C)2016 Elsevier Masson SAS。All rights reserved.
Approaches of targeting excessive activation and differentiation of osteoclasts were considered as an effective treatment option for osteoporosis or osteopenia. In the present work, a series of rhein derivatives were synthesized and employed for their cytotoxicity screening against bone marrow-derived macrophages cells (BMMs) and their inhibition effects on osteoclasts activation and differentiation in vitro using an MTF assay and a TRAP activity assay respectively. Two rhein derivatives d6 and d11 inhibited BMMs activation and differentiation with 98% and 85% inhibitory activity respectively, without showing any cytotoxicity on BMMs. Subsequently, the most potent compound d6 was further validated for its inhibitory effects on the formation of TRAP-positive multinucleated cells and bone resorption as evaluated by TRAP staining and bone resorption assay. The regulation by d6 of osteoclast marker genes assay revealed that treatment of BMMs with M-CSF and RANK!, resulted in the stimulation of mRNA expressions of NFATc1, c-fos, TRAP, MMP-9 and cathepsin K which were highly related with osteoclast activation and differentiation, while d6 decreased mRNA expressions of these genes. It was indicated that d6 might regulate osteoclasts activity through RANKL/RANK/NFATc1 pathway. Thus our current work is expected to provide a highly promising approach for the development of a new type of anti-osteoporosis agent. (C) 2016 Elsevier Masson SAS. All rights reserved.