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首页> 外文期刊>Cytokine >Proteasome inhibition suppress microgravity elevated RANK signaling during osteoclast differentiation
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Proteasome inhibition suppress microgravity elevated RANK signaling during osteoclast differentiation

机译：蛋白酶体抑制在破骨细胞分化期间抑制微沉降的级别信号传导

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摘要

Microgravity (mu Xg) induces bone loss in astronauts during space missions. Therefore, it is necessary to delineate the underlying mechanisms which leads to bone loss for developing countermeasures. Osteoclasts (OCLs) are multinucleated cells, which resorb bone. Previously, we have demonstrated that simulated mu Xg enhances OCL formation. However, control of osteoclast bone resorption activity under mu Xg remains unclear. The OCL formation has been shown to be regulated by ubiquitin-proteasome pathway. Hence, we hypothesized that proteasome inhibition could regulate osteoclast differentiation under mu Xg. In this study, we identified that RAW264.7 preosteoclast cells treated with proteasome inhibitor (MG-132) suppress RANK receptor expression essential for OCL differentiation, but no effect on TRAF-6. We identified that MG-132 treatment abolished K-48-linked poly-ubiquitination under mu Xg. Immunostaining confirms inhibition of protein ubiquitination and RANK expression in preosteoclast cells. Furthermore, proteasome inhibition suppresses the expression of SQSTM1/p62 under both the ground based Xg and mu Xg conditions. Also, confocal microscopy using Lyso-Tracker demonstrated that proteasomal inhibition suppress the co-localization of p62 and lysosomes. MG-132 inhibited RANKL induced proteasome activity. RAW264.7 cells treated with the proteasome inhibitor showed an increased level of p-c-Jun activity in control cultures, however decreased under mu Xg. In contrast, c-Fos and NFATc1 expression was decreased. In-addition, mouse bone marrow cultures treated with MG-132 suppress OCL formation and bone resorption activity. Thus, our findings suggest that proteasome inhibition represents a novel therapeutic approach for bone loss under mu Xg in space environment.
机译：微匍匐（MU XG）在太空任务期间诱导宇航员的骨质损失。因此，有必要描绘潜在的机制，这导致骨质损失以发展对策。骨核苷酸（OCL）是多核细胞，其再吸收骨。以前，我们已经证明了模拟MU XG增强了OCL形成。然而，控制MU XG下的骨细胞骨吸收活性的控制仍不清楚。已显示OCL形成由泛素 - 蛋白酶体途径调节。因此，我们假设蛋白酶体抑制可以调节u xg下的骨细胞分化。在这项研究中，我们鉴定了用蛋白酶体抑制剂（Mg-132）处理的Raw264.7预核醛细胞抑制了对OCL分化的等级受体表达，但对TRAF-6没有影响。我们认为Mg-132处理废除了Mu XG下的K-48连接的聚 - 泛菌素。免疫染色证实抑制蛋白质泛素化和碱性蛋白质中的含量。此外，蛋白酶体抑制在基于地基的XG和MU XG条件下抑制SQSTM1 / P62的表达。此外，使用Lyso-Tracker的共聚焦显微镜表明蛋白酶体抑制抑制p62和溶酶体的共定位。 MG-132抑制RANKL诱导的蛋白酶体活性。用蛋白酶体抑制剂处理的Raw264.7细胞显示在对照培养物中的p-C-Jun活性水平增加，但是在Mu xg下降低。相比之下，C-FOS和NFATC1表达减少。另外，用Mg-132处理的小鼠骨髓培养物抑制OCL形成和骨吸收活性。因此，我们的研究结果表明，蛋白酶体抑制代表了在空间环境中在MU XG下的骨质损失的新疗法方法。

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