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Study of the correlation bone in osteoclast resorption with atopic disease

破骨细胞吸收与特应性疾病相关性骨的研究

基本信息

批准号：
15390563
负责人：
KATO Yuzo
金额：
$ 9.54万
依托单位：
NAGASAKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390563/
关键词：
aspartic proteinase atopic disease cathepsin E Knockout mouse osteoclast signal transduction atonic disease Knockout mouse knockout mice

项目摘要

Receptor activator of nuclear factor kB (RANK) ligand (RANKL), expressed by osteoblastic cells, plays a pivotal role in osteoclastogenesis as well as in osteoclast activation and survival. After RANKL binds to its receptor, RANK, several tumor necrosis factor receptor-associated factors (TRAFs) bind directly to the cytoplasmic domain of RANK. The interaction between TRAF and RANK appears to be responsible for initiating the activation of most of the RANK-mediated signaling pathways such as NF-kB, Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3K) and calcium signaling pathways. RANK occupancy mobilizes intracellular calcium, a requisite for calcineurin-mediated nuclear factor activated T cells (NFAT) activation. NFAT binds to its DNA response element via a ternary complex with AP-1 proteins, including Fos/Jun, to transactivate target genes including tartrate-resistant acid phosph … More atase (TRAP). Thus NF-kB, AP-1 and NFAT play essential roles in osteoclast differentiation, fusion and activation. In this study, non-toxic concentrations of pepstatin A suppressed the osteoclastogenesis in a dose-dependent manner, especially in an early stage of osteoclast formation. The concentration of pepstatin A required for the suppression of osteoclast formation was higher than that for the complete inhibition of the aspartic proteinase activity in intact cells. Namely, the inhibition of osteoclastgenesis by pepstatin A was independent of the activity for cathepsin D. A cell signaling analyses indicated that the phosphorylation of ERK was inhibited in pepstatin A-treated cells, while the phosphorylation of IkB, Akt and p38 showed almost no change. Furthermore, pepstatin A decreased the expression of nuclear factor of activated T cell 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, and such actions are not due to the inhibition of the cathepsin D activity. Less

受体激活因子kB （Receptor activator of nuclear factor kB， RANK）配体（RANKL）由成骨细胞表达，在破骨细胞发生、破骨细胞活化和存活中起关键作用。在RANKL与其受体RANK结合后，几种肿瘤坏死因子受体相关因子（TRAFs）直接结合到RANK的细胞质结构域。TRAF和RANK之间的相互作用似乎负责启动大多数RANK介导的信号通路的激活，如NF-kB、Jun n-末端激酶（JNK）、p38丝裂原活化蛋白激酶（p38MAPK）、细胞外信号调节激酶（ERK）、磷脂酰肌醇-3激酶（PI3K）和钙信号通路。RANK占用调动细胞内钙，这是钙调磷酸酶介导的核因子活化T细胞（NFAT）活化的必要条件。NFAT通过与AP-1蛋白（包括Fos/Jun）的三元复合物结合到其DNA应答元件上，以反激活靶基因，包括抗酒石酸盐酸性磷酸酶（TRAP）。因此，NF-kB、AP-1和NFAT在破骨细胞分化、融合和活化过程中发挥着重要作用。在这项研究中，无毒浓度的胃抑素A以剂量依赖的方式抑制破骨细胞的发生，特别是在破骨细胞形成的早期阶段。抑制破骨细胞形成所需的胃抑素A浓度高于完全抑制完整细胞中天冬氨酸蛋白酶活性所需的浓度。也就是说，pepstatin A对破骨细胞生成的抑制与组织蛋白酶d的活性无关。细胞信号分析表明，在pepstatin A处理的细胞中，ERK的磷酸化被抑制，而IkB、Akt和p38的磷酸化几乎没有变化。此外，胃抑素A降低活化T细胞c1核因子（NFATc1）的表达。这些结果表明，胃抑素A通过阻断ERK信号通路和抑制NFATc1表达抑制破骨细胞的分化，而这种作用不是由于抑制组织蛋白酶D活性。少