2002 Fiscal Year Final Research Report Summary
Low Molecular Weight Compounds That Regulate Bone Metabolism
| Project/Area Number |
13460036
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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 |
応用微生物学・応用生物化学
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| Research Institution | Chubu University |
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Principal Investigator |
NAGAI Kazuo Chubu University Dept. of Biological Chemistry Professor, 応用生物学部, 教授 (00011974)
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| Co-Investigator(Kenkyū-buntansha) |
JE-TAE Woo Chubu University Dept. of Biological Chemistry Assistant Professor, 応用生物学部, 助教授 (20272693)
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| Project Period (FY) |
2001 – 2002
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| Keywords | destruxins / reveromycin A / EGCG / bone resorption / osteoclast / osteoporosis / cell death / calcium |
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| Research Abstract |
In the course of screening for the natural compounds in foods and microbial metabolites that prevent or cure osteoporosis, we found destruxins, reveromycin A (RMA) and (-)-Epigallocatechin-3-gallate (EGCG). Cyclodepsipeptides, destruxin B and E, were found to inhibit osteoclastic bone resorption without affecting osteoclast differentiation and survival. Destruxins reversibly induced morphological changes in functional osteoclasts in a dose-dependent manner. Electron microscopical analysis revealed that destruxin-treated osteoclasts on dentine slices have no prominent clear zones or ruffled borders. These results indicate that the anti-resorptive effects result from disorder of morphological structures in polarized osteoclasts induced by destruxins. RMA was found to inhibit bone resorption by inducing apoptosis in mature osteoclasts. The effect of RMA is accompanied by cytochrome c release from mitochondria into cytoplasm, caspase activation and nuclear fragmentation in osteoclasts. RMA
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induced apoptosis in activated osteoclasts having actin ring and resorption capability. The effect of RMA on activated osteoclasts was blocked by concanamycin B, a specific V-ATPase inhibitor or by acetazolamide, a carbonic anhydrase inhibitor, which prevents the acidification around the membrane of osteoclasts. RMA also inhibited the increase of serum calcium concentration induced by PTH injection in TPTX Rat. These results indicate that specific effect of RMA on activated osteoclasts results from acidic condition around the membrane of osteoclasts that increase cell permeability of RMA. Thus, RMA could be a good candidate for a new anti-resorptive osteoporotic medicine with high specificity against activated osteoclasts. EGCG specifically induced cell death in bone resorbing osteoclasts by promoting oxidative stress via Fenton reaction. Specific induction of apoptosis in osteoclasts by EGCG indicated the potentiality of EGCG as a prophylactic or therapeutic agent against osteoporosis. Less
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