Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras
Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras
复制标题
DOI：
10.1359/jbmr.1998.13.4.581
复制
发表时间：
1998-04-01
影响因子：
6.2
通讯作者：
Rogers, MJ
中科院分区：
文献类型：
--
作者：
Luckman, SP;Hughes, DE;Rogers, MJ
双膦酸盐是目前用于治疗代谢性骨病的最重要的一类抗骨吸收药物，虽然双膦酸盐的分子靶点尚未确定，但这些化合物通过可导致破骨细胞凋亡的机制抑制骨吸收，双膦酸盐也诱导体外小鼠J774巨噬细胞凋亡，可能通过导致破骨细胞凋亡的相同机制。我们发现，在J774巨噬细胞中，含氮双膦酸盐（如阿仑膦酸盐、伊班膦酸盐和利塞膦酸盐）抑制蛋白质的翻译后修饰（戊烯化），包括gtp结合蛋白Ras与法尼基或香叶基异戊二烯类基团，氯膦酸盐不抑制蛋白质的戊烯化，甲伐他汀是3-羟基-3-甲基谷氨酸(HMG)-CoA还原酶的抑制剂，因此是生产法尼基焦磷酸和香叶基焦磷酸所需的生物合成途径。此外，阿仑膦酸诱导的J774细胞凋亡与mevastatin诱导的J774细胞凋亡一样，可以通过添加焦磷酸法尼酯或焦磷酸香叶基香叶基来抑制，而阿仑膦酸对体外小鼠颅骨破骨细胞数量和骨吸收的影响可以通过添加甲羟戊酸来克服。这些观察结果表明，含氮双膦酸盐药物通过抑制Ras等蛋白质的翻译后戊烯酰化导致细胞凋亡。这些有效的抗骨吸收双膦酸盐也可能通过阻止破骨细胞中的蛋白质戊烯酰化来抑制骨吸收，甲羟戊酸途径的酶或戊烯酰蛋白转移酶是含氮双膦酸盐的分子靶点。此外，数据支持氯膦酸盐通过不同的机制起作用的观点。
Bisphosphonates are currently the most important class of antiresorptive drags used for the treatment of metabolic bone diseases, Although the molecular targets of bisphosphonates have not been identified, these compounds inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis, Bisphosphonates also induce apoptosis in mouse J774 macrophages in vitro, probably by the same mechanisms that lead to osteoclast apoptosis, We have found that, in J774 macrophages, nitrogen-containing bisphosphonates (such as alendronate, ibandronate, and risedronate) inhibit post-translational modification (prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl or geranylgeranyl isoprenoid groups, Clodronate did not inhibit protein prenylation, Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA reductase and hence the biosynthetic pathway required for the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in J774 macrophages and murine osteoclasts in vitro, Furthermore, alendronate-induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774 cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, while the effect of alendronate on osteoclast number and bone resorption in murine calvariae in vitro could be overcome by the addition of mevalonic acid, These observations suggest that nitrogen-containing bisphosphonate drugs cause apoptosis following inhibition of post-translational prenylation of proteins such as Ras, It is likely that these potent antiresorptive bisphosphonates also inhibit bone resorption by preventing protein prenylation in osteoclasts and that enzymes of the mevalonate pathway or prenyl protein transferases are the molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the data support the vie cv that clodronate acts by a different mechanism.