2000 Fiscal Year Final Research Report Summary
Microbial metabolites that regulate osteoclast differentiation and function
| Project/Area Number |
11660078
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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 | Tokyo Institute of Technology (TIT) |
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Principal Investigator |
NAGAI Kazuo Tokyo Institute of Technology, Graduate School of Bioscience and Biotechnology, Professor, 大学院・生命理工学研究科, 教授 (00011974)
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| Co-Investigator(Kenkyū-buntansha) |
禹 済泰 東京工業大学, 大学院・生命理工学研究科, 助手 (20272693)
WOO Je-tae Graduate School of Bioscience and Biotechnology Research Associate
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| Project Period (FY) |
1999 – 2000
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| Keywords | osteoclast / bone resorption / compactin / destruxins / reveromycin A / actin ring / apoptosis / cell fusion |
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| Research Abstract |
To obtain new insights into the mechanisms of differentiation and function of osteoclasts and to develop natural compounds as anti-resortive medicines for clinical application, we have screened microbial metabolites for low molecular weight compounds that inhibit the differentiation and function of osteoclasts. In the process of this screening we found compactin, destruxins and reveromycin A.Compactin inhibited the fusion process of prefusion osteoclasts into multinucleated osteoclasts, disrupted the actin ring of osteoclasts and inhibited bone resorption. The effects of compactin were suppressed by the addition of mevalonic acid lactone or its downastream products including farnesylpyrophosphate and gerahylgeranyl-pyrophosphate, but not by squalene. The results indicate that these effects of compactin are the consequence of the inhibition of prenylation of proteins that play an important role in the fusion process of preosteoclasts and in maintaining the actin ring integrity in osteoclasts. Destruxins, which are cyclomonodepsipeptides isolated from the antomogenous fungi, reversibly inhibited bone resorption through disrupting morphological structures including the actin ring in activated osteoclasts and inhibiting the polarization of osteoclasts on the bone without affecting viability of osteoclasts. They also affected the localization of c-src and a3 subunit of V-ATPase that are essential molecules osteoclasts. These results suggest that destruxins regulate polarization of osteoclasts. Reveromycin A induced apoptosis specifically in mature activated osteoclasts through release of mitochodrial cytochrome c into cytosol, and inhibited bone resorption. The specific effect of reveromycin A on activated osteoclasts was related to the acidic condition around membrane of activated osteoclasts.
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