| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Kuniaki Nagasaki University, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (10311846)
NISHISHITA Kazuhisa Nagasaki University, Research Associate, 大学院・医歯薬学総合研究科, 助手 (20237697)
SHIBATA Mitsue Nagasaki University, Research Associate, 大学院・医歯薬学総合研究科, 助手 (20274665)
SAKAI Eiko Nagasaki University, Research Associate, 大学院・医歯薬学総合研究科, 助手 (10176612)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2005: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Research Abstract |
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
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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
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