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2000 Fiscal Year Final Research Report Summary

Microbial metabolites that regulate osteoclast differentiation and function

Research Project

Project/Area Number 11660078
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用微生物学・応用生物化学
Research InstitutionTokyo Institute of Technology (TIT)

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)

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
Project Period (FY) 1999 – 2000
Keywordsosteoclast / bone resorption / compactin / destruxins / reveromycin A / actin ring / apoptosis / cell fusion
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.

  • Research Products

    (7 results)

All Other

All Publications (7 results)

  • [Publications] M.Takami: "Intracellular calcium and protein kinase C mediate expression of receptor activator of nuclear factor-kB ligand andosteoprotegerin in osteoclasts."Endocrinology. 141. 4711-4719 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] J.-T.Woo: "Compactin suppresses bone resorption by inhibiting the fusion of prefusion osteoclasts and disrupting the actin ring in osteoclasts."J.Bone Mineral Res.. 15. 650-662 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] J.-T.Woo: "RANKL and IL-1 induce the fusion of mononuclear preosteoclasts into multinucleated osteoclasts through their receptors by activating NF-κB."Cytotechnology. 33. 203-211 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Takami, J.-T.Woo and K.Nagai: "Osteoblastic cells induce fusion and activation of osteoclasts through a mechanism independent of macrophage-colony-stimulating factor production."Cell Tissue Res.. 298. 324-334 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Takami, N.Takahashi, N.Udagawa, C.Miyaura, K.Suda, J.-T.Woo, T.J.martin, K.Nagai, and T.Suda: "intracellular calcium and protein kinase C mediate expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in osteoclasts."Endocrinology. 141. 4711-4719 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] J.-T.Woo, M.Kasai P.H.Stern and K.Nagai: "compactin suppresses bone resorption by inhibiting the fusion of prefusion osteoclasts and disrupting the actin ring in osteoclasts."J.Bone Miner.Res.. 15. 650-662 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] J.-T.Woo, M.Takami, and K.Nagai: "RANKL and IL-1 induce the fusion of mononuclear preosteoclasts into multinucleated osteoclasts through their receptors by activating NF-kappaB."Cytotechnology. 33. 203-211 (2000)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2002-03-26  

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