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首页> 外文期刊>Journal of cellular biochemistry. >Effects of prelamin A processing inhibitors on the differentiation and activity of human osteoclasts.
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Effects of prelamin A processing inhibitors on the differentiation and activity of human osteoclasts.

机译:Prelamin A加工抑制剂对人破骨细胞分化和活性的影响。

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Osteoclast differentiation is a complex process involving cytoskeleton and nuclear reorganization. Osteoclasts regulate bone homeostasis and have a key role in bone degenerative processes. Osteolysis and osteoporosis characterize a subset of laminopathies, inherited disorders due to defects in lamin A/C. Laminopathies featuring bone resorption are characterized, at the molecular level, by anomalous accumulation of the unprocessed lamin A precursor, called prelamin A. To obtain a suitable cell model to study prelamin A effects on osteoclasts, prelamin A processing inhibitors FTI-277 or AFCMe were applied to peripheral blood monocytes induced to differentiate towards the osteoclastic lineage. Previous studies have shown that treatment with FTI-277 causes accumulation of non-farnesylated prelamin A, while AFCMe inhibition of prelamin A maturation causes accumulation of a farnesylated form. We demonstrate that monocytes subjected to FTI-277 treatment and mostly those subjected to AFCMe administration, differentiate towards the osteoclastic lineage more efficiently than untreated monocytes, in terms of number of multinucleated giant cells, mRNA expression of osteoclast-related genes and TRACP 5b activity. On the other hand, the bone resorption activity of osteoclasts obtained in the presence of high prelamin A levels is lower with respect to control osteoclasts. This finding may help the understanding of the osteolytic and osteoporotic processes that characterize progeroid laminopathies.
机译:破骨细胞分化是一个复杂的过程,涉及细胞骨架和核重组。破骨细胞调节骨骼的稳态,并在骨骼变性过程中起关键作用。骨质疏松和骨质疏松症是laminopathies的子集,这是由于lamin A / C缺陷导致的遗传性疾病。在分子水平上,以骨吸收为特征的椎间盘突出症的特征在于未加工的lamin A前体(称为prelamin A)的异常积累。为了获得合适的细胞模型来研究prelamin A对破骨细胞的作用,使用prelamin A加工抑制剂FTI-277或AFCMe应用于诱导分化为破骨细胞谱系的外周血单核细胞。以前的研究表明,用FTI-277进行治疗会导致非法呢基化的预醇溶蛋白A的积聚,而AFCMe抑制前味蛋白A的成熟会导致法尼基化形式的积聚。我们证明,在多核巨细胞的数量,破骨细胞相关基因的mRNA表达和TRACP 5b活性方面,经过FTI-277处理的单核细胞以及大多数经过AFCMe管理的单核细胞比未处理的单核细胞更有效地分化为破骨细胞谱系。另一方面,相对于对照破骨细胞,在高预乳蛋白A水平存在下获得的破骨细胞的骨吸收活性较低。这一发现可能有助于理解特征性早熟性椎体病的溶骨和骨质疏松过程。

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