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Regulation of osteoblastic differentiation by the proteasome inhibitor bortezomib

机译：蛋白酶体抑制剂硼替佐米对成骨细胞分化的调节

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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.
机译：在真核细胞中，大多数细胞内蛋白质的降解是通过泛素-蛋白酶体途径进行的。最近的研究表明，骨代谢也受该途径调节。硼替佐米是一种26S蛋白酶体抑制剂，被用作抗癌药，其临床疗效与骨形成的增加有关。在这项研究中，我们表明蛋白酶体抑制剂诱导C2C12细胞中成骨细胞分化相关基因（如骨钙素和碱性磷酸酶）的表达。相反，肌原性分化受到抑制。在测试的蛋白酶体抑制剂中，硼替佐米诱导了骨钙素表达的最大增加。尽管这些作用类似于骨形态发生蛋白（BMP）2，但蛋白酶体抑制剂不会诱导Smad1 / 4依赖的报告基因或BMP2信号传导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。骨钙蛋白启动子的OSE2位点（而非OSE1位点）的突变减少了硼替佐米诱导的活性。同样，通过硼替佐米治疗诱导Runx2结合活性和蛋白质水平。这些结果表明，硼替佐米通过修饰Runx2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。

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