Lipophilic statins can be osteogenic by promoting osteoblastic calcification in a Cbfa1-and BMP-2-independent manner
Lipophilic statins can be osteogenic by promoting osteoblastic calcification in a Cbfa1-and BMP-2-independent manner
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DOI：
10.1358/mf.2001.23.7.662123
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发表时间：
2001-09-01
影响因子：
--
通讯作者：
Koida, M
中科院分区：
文献类型：
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作者：
Izumo, N;Fujita, T;Koida, M
无论有无3 mM无机磷刺激，美伐他汀(3-10um)和氟伐他汀(0.1-10um)均可促进MC3T3-E1细胞及其亚克隆MC4的钙化，但普伐他汀无此作用。并对其作用机理进行了探讨。凝胶滞留分析和核心结合因子(Cbfa1)的免疫细胞化学分析表明，美伐他汀和氟伐他汀完成了Cbfa1的核输出，从而可能减少了稳定表达的p60SE2-Luc基因的诱导，进而促进了Cbfa1非依赖性钙化，这在野生型和显性阴性Cbfa1表达的细胞中都存在。骨形态发生蛋白-2(BMP-2)基因启动子的诱导不能对他汀类药物产生反应。甲氧戊酸途径的代谢产物(香叶基香叶基焦磷酸；法尼基焦磷酸>；甲氧丙酮酸)可抵消他汀类药物的所有细胞通透性作用，并可被B毒素(一种Rho特异性抑制剂)复制，但不能完全被Y27632(一种岩石特异性抑制剂)所抑制。结果表明，亲脂性他汀类药物可以通过促进Cbfa1和BMP-2非依赖的钙化过程而成骨。(C)2001年《岩石科学》。版权所有。
Mevastatin (3-10 muM) and fluvastatin (0.1-10 muM), but not pravastatin, were found to promote calcification of MC3T3-E1 cells and their subclone MC4, in either the presence or absence of 3 mM inorganic phosphate stimulus. The mechanism of action was examined. Gel retardation assay and immunocytochemical analysis of core binding factor (Cbfa1) revealed that mevastatin and fluvastatin completed the nuclear export of Cbfa1, possibly thereby reducing the induction of the stably transfected p60SE2-luc gene, and then promoted Cbfa1-independent calcification, which invariably occurred in both wild type and dominant negative Cbfa1-expressing cells. The induction of the bone morphogenetic protein-2 (BMP-2) gene promoter failed to respond to the statins. All the effects of the cell-permeable statins were negated by mevalonate pathway metabolites (geranylgeranylpyrophosphate > farnesylpyrophosphate > mevalonate) and reproduced by toxin B (a Rho-specific inhibitor), but not totally by Y27632 (a ROCK-specific inhibitor). The results suggest that lipophilic statins can be osteogenic by promoting Cbfa1- and BMP-2-independent calcification processes. (C) 2001 Prous Science. All rights reserved.