Arctigenin inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways.
Arctigenin inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways.
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DOI：
10.1371/journal.pone.0085878
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Takahashi N
中科院分区：
文献类型：
--
作者：
Yamashita T;Uehara S;Udagawa N;Li F;Kadota S;Esumi H;Kobayashi Y;Takahashi N
牛蒡子苷元是牛蒡子种子中的一种成分，是一种木脂素衍生的化合物。牛蒡子苷元以前被证明能抑制破骨细胞的生成，然而，这种抑制机制尚未阐明。在这里，我们发现牛蒡子苷元抑制活化T细胞的核因子，胞质1（NFATc1），破骨细胞生成的关键转录因子的行动。破骨细胞前体中的NFATc1通过两种不同的途径激活：钙调神经磷酸酶依赖性和成骨细胞依赖性途径。在所检测的几种木脂素衍生化合物中，牛蒡子苷元最强烈地抑制了小鼠骨髓巨噬细胞（BMM）培养物中核因子κ B配体（RANKL）受体激活剂诱导的破骨细胞样细胞形成，其中钙调神经磷酸酶依赖性NFATc 1途径被激活。牛蒡子苷元既不抑制核因子κ B和丝裂原活化蛋白激酶的活化，也不抑制RANKL处理的Bp53中c-Fos表达的上调。然而，牛蒡子苷元抑制RANKL诱导的NFATc1表达。有趣的是，用牛蒡子苷元处理破骨细胞样细胞将NFATc1转化为较低分子量的物质，即使在不存在RANKL的情况下，NFATc1也易位到细胞核中。然而，牛蒡子苷元以及环孢菌素A（CsA），钙调磷酸酶抑制剂，抑制NFAT-荧光素酶报告活性诱导的离子霉素和佛波醇12-肉豆蔻酸酯13-乙酸酯在甜菜碱。染色质免疫沉淀分析证实，牛蒡子苷元抑制NFATc1的NFATc1靶基因的启动子区域的招聘。牛蒡子苷元，而不是CsA抑制破骨细胞样细胞的形成，在共培养的成骨细胞和骨髓细胞，其中成骨细胞依赖的NFATc1途径被激活。强制表达的组成性活性NFATc1救出破骨细胞在BMM文化与CsA治疗，但不是与牛蒡子苷元治疗。牛蒡子苷元还抑制了在牙本质切片上培养的破骨细胞样细胞的窝形成活性。这些结果表明，牛蒡子苷元诱导的NFATc1，抑制破骨细胞的分化和功能，抑制钙调神经磷酸酶依赖性和成骨细胞依赖性NFATc1途径的显性负物种。
Arctigenin, a lignan-derived compound, is a constituent of the seeds of Arctium lappa. Arctigenin was previously shown to inhibit osteoclastogenesis; however, this inhibitory mechanism has yet to be elucidated. Here, we showed that arctigenin inhibited the action of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key transcription factor for osteoclastogenesis. NFATc1 in osteoclast precursors was activated through two distinct pathways: the calcineurin-dependent and osteoblastic cell-dependent pathways. Among the several lignan-derived compounds examined, arctigenin most strongly inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast-like cell formation in mouse bone marrow macrophage (BMM) cultures, in which the calcineurin-dependent NFATc1 pathway was activated. Arctigenin suppressed neither the activation of nuclear factor κB and mitogen-activated protein kinases nor the up-regulation of c-Fos expression in BMMs treated with RANKL. However, arctigenin suppressed RANKL-induced NFATc1 expression. Interestingly, the treatment of osteoclast-like cells with arctigenin converted NFATc1 into a lower molecular weight species, which was translocated into the nucleus even in the absence of RANKL. Nevertheless, arctigenin as well as cyclosporin A (CsA), a calcineurin inhibitor, suppressed the NFAT-luciferase reporter activity induced by ionomycin and phorbol 12-myristate 13-acetate in BMMs. Chromatin immunoprecipitation analysis confirmed that arctigenin inhibited the recruitment of NFATc1 to the promoter region of the NFATc1 target gene. Arctigenin, but not CsA suppressed osteoclast-like cell formation in co-cultures of osteoblastic cells and bone marrow cells, in which the osteoblastic cell-dependent NFATc1 pathway was activated. The forced expression of constitutively active NFATc1 rescued osteoclastogenesis in BMM cultures treated with CsA, but not that treated with arctigenin. Arctigenin also suppressed the pit-forming activity of osteoclast-like cells cultured on dentin slices. These results suggest that arctigenin induces a dominant negative species of NFATc1, which inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways.
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11.4
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