Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation.
Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation.
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DOI：
10.1186/1423-0127-21-10
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发表时间：
2014-02-03
影响因子：
11
通讯作者：
Nishida S
中科院分区：
文献类型：
--
作者：
Tsubaki M;Komai M;Itoh T;Imano M;Sakamoto K;Shimaoka H;Takeda T;Ogawa N;Mashimo K;Fujiwara D;Mukai J;Sakaguchi K;Satou T;Nishida S
双膦酸盐是一类重要的抗骨吸收药物，用于治疗代谢性骨病。最近的研究表明，含氮双膦酸盐可诱导兔破骨细胞凋亡，并阻止戊烯基化小GTPase。然而，双膦酸盐是否抑制破骨细胞的形成尚未确定。在本研究中，我们研究了米诺膦酸钠和阿仑膦酸钠对小鼠巨噬细胞样细胞系C7和RAW264.7的破骨细胞形成的抑制作用，并阐明了其机制。发现米诺膦酸钠和阿仑膦酸钠能抑制NF-κB配体受体激活剂和巨噬细胞集落刺激因子诱导的C7细胞破骨细胞的形成，而这两种细胞是通过抑制香叶香叶酰焦磷酸（GGPP）的生物合成而被抑制的。同时发现米诺膦酸钠和阿仑膦酸钠抑制NF-κB配体受体激活剂诱导的RAW264.7细胞破骨细胞的形成。此外，米诺膦酸钠和阿仑多酸钠降低磷酸化的细胞外信号调节激酶1/2 （ERK1/2）和Akt；同样，有丝分裂原蛋白激酶1/2 （MEK1/2）抑制剂U0126和磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002抑制破骨细胞的形成。这表明米诺膦酸钠和阿仑膦酸钠通过甲羟戊酸途径抑制GGPP的生物合成，进而抑制MEK/ERK和PI3K/Akt途径的信号转导，从而抑制破骨细胞的形成。这些结果表明，双膦酸盐可能有效治疗骨代谢疾病，如骨质疏松症。
Bisphosphonates are an important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Recent studies have shown that nitrogen-containing bisphosphonates induced apoptosis in rabbit osteoclasts and prevented prenylated small GTPase. However, whether bisphosphonates inhibit osteoclast formation has not been determined. In the present study, we investigated the inhibitory effect of minodronate and alendronate on the osteoclast formation and clarified the mechanism involved in a mouse macrophage-like cell lines C7 and RAW264.7. It was found that minodronate and alendronate inhibited the osteoclast formation of C7 cells induced by receptor activator of NF-κB ligand and macrophage colony stimulating factor, which are inhibited by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. It was also found that minodronate and alendronate inhibited the osteoclast formation of RAW264.7 cells induced by receptor activator of NF-κB ligand. Furthermore, minodronate and alendornate decreased phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; similarly, U0126, a mitogen protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited osteoclast formation. This indicates that minodronate and alendronate inhibit GGPP biosynthesis in the mevalonate pathway and then signal transduction in the MEK/ERK and PI3K/Akt pathways, thereby inhibiting osteoclast formation. These results suggest a novel effect of bisphosphonates that could be effective in the treatment of bone metabolic diseases, such as osteoporosis.
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影响因子：
4.1
作者：
Russell, RGG;Rogers, MJ
通讯作者：
Rogers, MJ
影响因子：
8.4
作者：
Neville-Webbe, H. L.;Coleman, R. E.
通讯作者：
Coleman, R. E.
影响因子：
7.4
作者：
Sevcik, MA;Luger, NM;Mantyh, PW
通讯作者：
Mantyh, PW
影响因子：
20.3
作者：
Dai, XM;Ryan, GR;Stanley, ER
通讯作者：
Stanley, ER
影响因子：
4
作者：
Clezardin, Philippe;Teti, Anna
通讯作者：
Teti, Anna