2006 Fiscal Year Final Research Report Summary
The studies of action mechanism and pharmacological effect of anti-resorptive compounds that target osteocasts.
| Project/Area Number |
17380069
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied biochemistry
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| Research Institution | Chubu University |
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Principal Investigator |
NAGAI Kazuo Chubu University, College of Bioscience and Biotechnology, Professor, 応用生物学部, 教授 (00011974)
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| Co-Investigator(Kenkyū-buntansha) |
WOO Je-Tae Chubu University, College of Bioscience and Biotechnology, Professor, 応用生物学部, 教授 (20272693)
OHNISHI Motoko Chubu University, College of Bioscience and Biotechnology, Associate Professor, 応用生物学部, 助教授 (00312653)
MINAMI Motoyasu Chubu University, College of Bioscience and Biotechnology, Associate Professor, 応用生物学部, 助教授 (90340207)
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| Project Period (FY) |
2005 – 2006
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| Keywords | reveromycin A / curcumin / nepodin / bone resorption / osteoclast / osteoporosis / EGCG / triphenyltin |
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| Research Abstract |
Reveromycin A (RM-A) induced apoptosis specifically in OCs, but not in OC progenitors, nonfunctional osteoclasts, or osteoblasts. One of its target molecules was isoleucy1-tRNA synthetase in osteoclasts. RM-A inhibited osteoclastic pit formation, decreased prelabeled (45)Ca release in organ cultures, and antagonized increased bone resorption in ovariectomized mice. These results suggested that preventive effects of RM-A on bone resorption were caused by apoptosis through inhibition of isoleucy1-tRNA synthetase in OCs and that specific sensitivity of OCs to RM-A was due to the acidic microenvironment, which increased cell permeability of RM-A by suppressing dissociation of protons from carboxylic acid moieties, making them less polar. This unique mechanism suggested that RM-A might represent a type of therapeutic agent for treating bone disorders associated with increased bone loss. (-)-Epigallocatechin gallate (EGCG) induces cell death of osteoclasts in an Fe(2+)-and H(2)O(2)-dependent
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manner. Molecules methylated at position 4' in the B ring (EGCG-4'-O-Me) or at position 4" in the D-ring (EGCG-4"-O-Me) showed markedly decreased cytotoxicity to osteoclasts, indicating that hydroxyl groups at these two positions of EGCG are crucial for inducing cell death of osteoclasts. EGCG-4'-O-Me also showed the lowest Fe(3+)-reducing activity among five EGCGs. These results suggest that the highest occupied molecular orbital (HOMO) on the B-ring plays crucial roles in the cytotoxicity of EGCG to osteoclasts. Tributyltin (TBT) and triphenyltin (TPT) dose-dependently inhibited osteoclast differentiation at concentrations of 3-30 nM. Treatment with a retinoic acid receptor (RAR)-specific antagonist, Ro41-5253, restored the inhibition of osteoclastogenesis by TBT and TPT. TBT and TPT reduced receptor activator of nuclear factor-kappaB ligand (RANKL) induced nuclear factor of activated T cells (NFAT) cl expression, and the reduction in NFATcl expression was recovered by Ro41-5253. Our results suggest that TBT and TPT suppress osteoclastogenesis by inhibiting RANKL-induced NFATcl expression via an RAR-dependent signaling pathway. Less
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