Study of the correlation bone in osteoclast resorption with atopic disease

核因子kB受体激活剂(RANKL)由成骨细胞表达，在破骨细胞的形成以及破骨细胞的活化和存活中起着关键作用。在RANKL与其受体RANK结合后，几个肿瘤坏死因子受体相关因子(TRAF)直接与RANK的胞浆结构域结合。TRAF和RANK之间的相互作用可能是RAN介导的大多数信号通路如核因子-kB、Jun氨基末端激酶(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)和钙信号通路的启动因素。RANK占位动员细胞内钙，钙调神经磷酸酶介导的核因子激活T细胞(NFAT)所必需的。NFAT通过与AP-1蛋白(包括Fos/Jun)的三元复合体与其dna反应元件结合，反式激活包括酒石酸抗性酸性磷酸…在内的靶基因更多的是(陷阱)。因此，NF-kB、AP-1和NFAT在破骨细胞的分化、融合和激活中起重要作用。在本研究中，无毒浓度的胃抑素A以剂量依赖的方式抑制破骨细胞的形成，尤其是在破骨细胞形成的早期阶段。在完整细胞中，抑制破骨细胞形成所需的胃抑素A浓度高于完全抑制天冬氨酸蛋白酶活性所需的浓度。也就是说，胃抑素A对破骨细胞生成的抑制作用不依赖于组织蛋白酶D的活性。细胞信号分析表明，胃抑素A处理的细胞中ERK的磷酸化受到抑制，而IkB、Akt和p38的磷酸化几乎没有变化。此外，胃抑素A还可降低活化T细胞核因子C1FATc1的表达。这些结果提示胃抑素A通过阻断ERK信号通路和抑制NFATc1的表达来抑制破骨细胞的分化，这种作用不是通过抑制组织蛋白酶D的活性实现的。较少

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