Pepstatin A, an aspartic proteinase inhibitor, suppresses RANKL-induced osteoclast differentiation.
Pepstatin A, an aspartic proteinase inhibitor, suppresses RANKL-induced osteoclast differentiation.
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DOI：
10.1093/jb/mvj066
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发表时间：
2006-03
影响因子：
2.7
通讯作者：
H. Yoshida;K. Okamoto;Tsutomu Iwamoto;E. Sakai;K. Kanaoka;Jin-Ping Hu;M. Shibata;H. Hotokezaka;K. Nishishita;A. Mizuno;Y. Kato
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文献类型：
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作者：
H. Yoshida;K. Okamoto;Tsutomu Iwamoto;E. Sakai;K. Kanaoka;Jin-Ping Hu;M. Shibata;H. Hotokezaka;K. Nishishita;A. Mizuno;Y. Kato
众所周知，胃蛋白酶抑制素A是天冬氨酸蛋白酶如胃蛋白酶、组织蛋白酶D和E的抑制剂。然而，除了作为蛋白酶抑制剂的作用外，胃酶抑素A对细胞的药理作用尚不清楚。在这项研究中，我们发现胃酶抑素A抑制NF-κ B配体受体激活剂（RANKL）诱导的破骨细胞分化。胃酶抑素A抑制多核破骨细胞的形成呈剂量依赖性。这种对形成的抑制仅影响破骨细胞，即，而不是成骨细胞样细胞。此外，胃酶抑素A也抑制前破骨细胞分化为单核破骨细胞的剂量依赖性。这种抑制似乎与蛋白酶如组织蛋白酶D的活性无关，因为在抑制组织蛋白酶D活性的浓度下，破骨细胞的形成不受抑制。细胞信号转导分析表明，在胃蛋白酶抑制剂A处理的细胞中，ERK的磷酸化受到抑制，而IkappaB和Akt的磷酸化几乎没有变化。此外，胃酶抑素A降低活化T细胞核因子c1（NFATc 1）的表达。这些结果表明，胃酶抑素A通过阻断ERK信号和抑制NFATc 1表达来抑制破骨细胞的分化。
Pepstatin A is well known to be an inhibitor of aspartic proteinases such as pepsin, cathepsins D and E. Except for its role as a proteinase inhibitor, however, the pharmacological action of pepstatin A upon cells remain unclear. In this study, we found that pepstatin A suppressed receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation. Pepstatin A suppressed the formation of multinuclear osteoclasts dose-dependently. This inhibition of the formation only affected osteoclast cells, i.e., not osteoblast-like cells. Furthermore, pepstatin A also suppressed differentiation from pre-osteoclast cells to mononuclear osteoclast cells dose-dependently. This inhibition seems to be independent of the activities of proteinases such as cathepsin D, because the formation of osteoclasts was not suppressed with the concentration that inhibited the activity of cathepsin D. Cell signaling analysis indicated that the phosphorylation of ERK was inhibited in pepstatin A-treated cells, while the phosphorylation of IkappaB and Akt showed almost no change. Furthermore, pepstatin A decreased the expression of nuclear factor of activated T cells c1 (NFATc1). These results suggest that pepstatin A suppresses the differentiation of osteoclasts through the blockade of ERK signaling and the inhibition of NFATc1 expression.