2003 Fiscal Year Final Research Report Summary
Studies on action mechanism of microbial metabolites that specifically inhibit osteoclastic bone resorption.
| Project/Area Number |
14560079
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 |
WOO Je-tae Chubu University, College of Bioscience and Biotechnology, Associate Professor, 応用生物学部, 助教授 (20272693)
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| Co-Investigator(Kenkyū-buntansha) |
OHNISI Motoko Chubu University, College of Bioscience and Biotechnology, Associate Professor, 応用生物学部, 助教授 (00312653)
NAGAI Kazuo Chubu University, College of Bioscience and Biotechnology, Professor, 応用生物学部, 教授 (00011974)
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| Project Period (FY) |
2002 – 2003
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| Keywords | osteoclast / bone resorption / osteoporosis / apoptosis / reveromycin A / destruxin / microbial metabolite / action mechanism |
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| Research Abstract |
In the course of screening for the natural compounds that prevent or cure osteoporosis, we found destruxins, reveromycin A (RMA) in microbial metabolites that are targeted to the function and survival of mature osteoclats. Cyclodepsipeptides, destruxin B and E, were found to inhibit osteoclastic bone resorption without affecting osteoclast differentiation and survival, and RMA was found to induce apoptosis in mature osteoclasts, not in osteoclast progenitor cells, mononuclear preosteoclasts and inactivated osteoclasts. In the present study, we investigated their mechanism of action on mature osteoclasts and their inhibitory effect on the increase of serum calcium concentration induced by PTH injection in TPTX Rat. The effect of RM-A was decreased by disruption of the acidic microenvironment in activated osteoclasts, but is increased in acidic culture condition. The apoptotic effect of RM-A was decreased by methylation of the carboxylic acid moiety. 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 conditions around the membrane of osteoclasts that increase cell permeability of RMA, and that RMA could be a good candidate for a new anti-resorptive medicine with high specificity against activated osteoclasts. The culture condition for high amount of destruxin E production was developed. We found that in a new culture condition selected from 60 kinds of medium composition, the strain produces by about 100 mg/L destruxin E and we obtained about 600 mg of purified sample that is enough for studying its action mechanism and in vivo effcets.
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