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首页> 外文期刊>Journal of orthopaedic research >CA-074Me compound inhibits osteoclastogenesis via suppression of the NFATc1 and c-FOS signaling pathways
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CA-074Me compound inhibits osteoclastogenesis via suppression of the NFATc1 and c-FOS signaling pathways

机译：CA-074Me化合物通过抑制NFATc1和c-FOS信号通路抑制破骨细胞生成

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The osteoclast is an integral cell of bone resorption. Since osteolytic disorders hinge on the function and dysfunction of the osteoclast, understanding osteoclast biology is fundamental to designing new therapies that curb osteolytic disorders. The identification and study of lysosomal proteases, such as cathepsins, have shed light on mechanisms of bone resorption. For example, Cathepsin K has already been identified as a collagen degradation protease produced by mature osteoclasts with high activity in the acidic osteoclast resorption pits. Delving into the mechanisms of cathepsins and other osteoclast related compounds provides new targets to explore in osteoclast biology. Through our anti-osteoclastogenic compound screening experiments we encountered a modified version of the Cathepsin B inhibitor CA-074: the cell membrane-permeable CA-074Me (L-3-trans-(Propylcarbamoyl) oxirane-2-carbonyl]-L-isoleucyl-L-proline Methyl Ester). Here we confirm that CA-074Me inhibits osteoclastogenesis in vivo and in vitro in a dose-dependent manner. However, Cathepsin B knockout mice exhibited unaltered osteoclastogenesis, suggesting a more complicated mechanism of action than Cathepsin B inhibition. We found that CA-074Me exerts its osteoclastogenic effect within 24h of osteoclastogenesis stimulation by suppression of c-FOS and NFATc1 pathways. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1474-1486, 2015.
机译：破骨细胞是骨吸收的整体细胞。由于溶骨性疾病取决于破骨细胞的功能和功能障碍，因此了解破骨细胞生物学对于设计抑制溶骨性疾病的新疗法至关重要。溶酶体蛋白酶（例如组织蛋白酶）的鉴定和研究为骨骼吸收的机理提供了启示。例如，组织蛋白酶K已经被鉴定为由成熟的破骨细胞产生的胶原降解蛋白酶，该破骨细胞在酸性破骨细胞吸收凹坑中具有高活性。深入研究组织蛋白酶和其他破骨细胞相关化合物的机制，为破骨细胞生物学研究提供了新的靶标。通过我们的抗破骨细胞生成化合物筛选实验，我们遇到了组织蛋白酶B抑制剂CA-074的改良版：细胞膜可渗透的CA-074Me（L-3-反式-（丙基氨基甲酰基）环氧乙烷-2-羰基] -L-异亮氨酸-L-脯氨酸甲基酯）。在这里，我们证实CA-074Me在体内和体外以剂量依赖性方式抑制破骨细胞生成。但是，组织蛋白酶B基因敲除小鼠表现出破骨细胞生成未改变，提示其作用机制比组织蛋白酶B抑制更为复杂。我们发现，CA-074Me通过抑制c-FOS和NFATc1途径发挥其破骨细胞作用。 （c）2015骨科研究学会。由Wiley Periodicals，Inc.出版，J Orthop Res 33：1474-1486，2015。

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