Regulation of osteoblastic differentiation by the proteasome inhibitor bortezomib.
Regulation of osteoblastic differentiation by the proteasome inhibitor bortezomib.
复制标题
蛋白酶体抑制剂硼替佐米对成骨细胞分化的调节。
DOI：
10.1111/j.1365-2443.2012.01611.x
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发表时间：
2012
期刊：
影响因子：
2.1
通讯作者：
Uyama M
中科院分区：
文献类型：
--
作者：
Uyama M;Sato MM;Kawanami M;Tamura M;Taichi Kamiunten;Uyama M
在真核细胞中，大多数细胞内蛋白质的降解通过泛素-蛋白酶体途径进行。最近的研究表明，骨代谢也受到这一途径的调节。硼替佐米是一种用作抗癌药物的26 S蛋白酶体抑制剂，其临床疗效与骨形成的增加有关。在这项研究中，我们发现蛋白酶体抑制剂诱导成骨细胞分化相关基因的表达，如骨钙素和碱性磷酸酶在C2 C12细胞。相反，成肌分化受到抑制。在测试的蛋白酶体抑制剂中，硼替佐米诱导骨钙素表达的最大增加。虽然这些作用与骨形态发生蛋白（BMP）2相似，但蛋白酶体抑制剂不会诱导Smad 1/4依赖性报告基因或BMP 2信号靶基因表达的转录活性。用硼替佐米瞬时转染骨钙素启动子-荧光素酶构建体导致荧光素酶活性增加。骨钙素启动子的OSE 2位点突变（而非OSE 1位点突变）减弱了硼替佐米诱导的活性。此外，Runx 2结合活性和蛋白质水平诱导硼替佐米治疗。这些结果表明硼替佐米通过改变Runx 2的活性诱导成骨细胞分化，并且蛋白酶体在控制分化相关转录因子降解中的功能在成骨细胞分化中起重要作用。
In eukaryotic cells, degradation of most intracellular proteins is carried out by the ubiquitin‐proteasome pathway. Recent investigations suggest that bone metabolism is also regulated by this pathway. The clinical efficacy of bortezomib, a 26S proteasome inhibitor used as an anticancer drug, has been linked to an increase in bone formation. In this study, we show that proteasome inhibitors induce expression of osteoblastic differentiation‐related genes such as osteocalcin and alkaline phosphatase in C2C12 cells. In contrast, myogenic differentiation is inhibited. Among the proteasome inhibitors tested, bortezomib induced the greatest increase in osteocalcin expression. Although these effects were similar to that of bone morphogenetic protein (BMP) 2, proteasome inhibitors did not induce transcriptional activity of Smad1/4‐dependent reporter or BMP2 signaling target gene expression. Transient transfection of osteocalcin promoter‐luciferase constructs with bortezomib resulted in an increase in luciferase activity. Mutation of OSE2, but not OSE1, sites of the osteocalcin promoter diminished the bortezomib‐induced activity. Also, Runx2 binding activity and protein levels were induced by bortezomib treatment. These results suggest that the bortezomib induces osteoblastic differentiation by modifying the activity of Runx2 and that the function of the proteasome in controlling degradation of differentiation‐related transcription factors plays an important role in osteoblast differentiation.