A Search and their action mode of microbial bioactive compounds that inhibit osteoclastic Bone Resorption.

• Project/Area Number: 16580065
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied microbiology
• Research Institution: Chubu University
• Principal Investigator: WOO Je Tae Chubu University, College of Bioscience and Biotechnology, Professor, 応用生物学部, 教授 (20272693)
• Co-Investigator(Kenkyū-buntansha): NAGAI Kazuo Chubu University, College of Bioscience and Biotechnology, Professor, 応用生物学部, 教授 (00011974) ; OHNISHI Motoko Chubu University, College of Bioscience and Biotechnology, Assistant Professor, 応用生物学部, 助教授 (00312653)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: destruxins / reveromycin A / compactin / bone resorption / osteoclast / osteoporosis / coptisine / berberine / 代謝産物 / アルカロイド / ベロマイシン / 細胞骨格 / 骨密度 / 微生物代謝産物 / 機能発現

Research Abstract

In the present study, we determined action mode of reveromycin A (RMA), compactin (mevastatin) and destruxins in cell and molecular level on osteoclast differentiation and function, and screened new compounds from herbs that inhibit osteoclast differentiation. The target molecular of RMA is isoleusyl tRNA synthetase and the selective effect of RM-A on activated osteoclasts is due to the acidified microenviroment which is derived by activated osteoclast. RMA also inhibited the increase of bone resorption in ovariectomised mice. These results indicate that RMA could be a good candidate for a new anti-resorptive medicine with high specificity against activated osteoclasts. Mevastatin was shown to inhibit early differentiation of osteoclasts from their progenitor by decreasing geranylgeranyl pyrophosphate in the pathway of cholesterol synthesis. Geranylgeranyl transferase inhibitor inhibited the geranylgeranylation of small G-protein, suggesting that the geranylgeranylation of small G-protein is involved in the inhibitory effect of mevastatin on early differentiation of osteoclasts. Alkaloids, coptisine (from Coptidis Rhizoma) and berberine (Corydalis Tuber) were found to inhibit osteoclast differentiation. These compounds inhibited osteoclast differentiation by blocking the increase of expression of NFAT which is an essential transcription factor for osteoclast differentiation.

Research Products

• [Journal Article] Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts. (2006)
  • Author(s): Woo JT, Kawatani M, Kato M, Shinki T, Lee KH, Stern PH, Nagai K, Osada H (他4人)Takami M, Lee KH, Stern PH, Nagai K, Osada H
  • Journal Title: Proc Natl Acad Sci U S A. 13. 103 Pages: 4729-4734
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Curcumin inhibits the proliferation and mineralization of cultured osteoblasts. (2006)
  • Author(s): Notoya M, Nishimura H, Woo JT, Nagai K, Ishihara Y, Hagiwara H, N.Udagawa, In-Sun Lee, Motoko Ohnishi, Hiromi Hagiwara, Kazuo Nagai
  • Journal Title: Eur J Pharmacol. 534 Pages: 55-62
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts. (2006)
  • Author(s): Woo JT, Kawatani M, Kato M, Shinki T, Yonezawa T, Kanoh N, Nakagawa H, Takami M, Lee KH, Stern PH, Nagai K, Osada H.
  • Journal Title: Proc Natl Acad Sci USA. 103(12) Pages: 4729-4734
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Curcumin inhibits the proliferation and mineralization of cultured osteoblasts. (2006)
  • Author(s): Notoya M, Nishimura H, Woo JT, Nagai K, Ishihara Y, Hagiwara H.
  • Journal Title: Eur J Pharmacol. 534 Pages: 55-62
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Curcumin inhibits the proliferation and mineralization of cultured osteoblasts. (2006)
  • Author(s): Notoya M, Nishimura H, Woo JT, Nagai K, Ishihara Y, Hagiwara H
  • Journal Title: Eur J Pharmacol. 534 Pages: 55-62
• [Journal Article] Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts. (2006)
  • Author(s): Woo JT, Kawatani M, Kato M, Shinki T, Stern PH, Nagai K, Osada H.
  • Journal Title: Proc Natl Acad Sci U S A. 13. 103 Pages: 4729-4734
• [Journal Article] Statins and geranylgeranyl transferase I inihibitor inhibit mononuclear osteoclast formation induced by RANKL and TNF. (2005)
  • Author(s): Je-Tae Woo, Hiroshi Nakagawa, Annette M.Krecic, Kazuo Nagai, Andrew D.Hamilton, Said M.Sebti, Paula H.Stern
  • Journal Title: Biochemical Pharmacology, 69 Pages: 87-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Statins and geranylgeranyl transferase I inihibitor inhibit mononuclearosteoclast formation induced by RNAKL and TNF (2005)
  • Author(s): J-T Woo, H.Nakagawa, A.M.Krecic, K.Nagai, A.D.Hamilton, S.M.Sebti, P.H.Stern
  • Journal Title: Biochemical Pharmacology 69 Pages: 87-95
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Statins and geranylgeranyl transferase I inihibitor inhibit mononuclear osteoclast formation induced by RANKL and TNF. (2005)
  • Author(s): Je-Tae Woo, Hiroshi Nakagawa, Annette M.Krecic, Kazuo Nagai, Andrew D.Hamilton
  • Journal Title: Biochemical Pharmacology, 69 Pages: 87-95
• [Journal Article] Statins and geranylgeranyl transferase I inhibitor inhibit mononuclear osteoclast formation induced by RANKL and TNF. (2005)
  • Author(s): Je-Tae Woo, Hiroshi Nakagawa, Annette M.Krecic, Kazuo Nagai
  • Journal Title: Biochemical Pharmacology 69 Pages: 87-95
• [Journal Article] Generation of hydrogen peroxide primarily contributes to the induction of Fe(II)-dependent apoptosis in Jurkat cells by(-)-epigallocatechin gallate. (2004)
  • Author(s): Nakagawa H, Hasumi K, Woo JT, Nagai K, Wachi M.
  • Journal Title: Carcinogenesis. 25 Pages: 1567-1574
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cyclosporine A and FK506 induce osteoclast apoptosis in mouse bone marrow cell cultures. (2004)
  • Author(s): Igarashi K, Hirotani H, Woo JT, Stern PH.
  • Journal Title: Bone 35 Pages: 47-56
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Symbioimine Exhibiting Inhibitory Effect of Osteoclast Differentiation, from the Symbiotic Marine Dinoflagellate Symbiodinium sp. (2004)
  • Author(s): Kita M, Kondo M, Koyama T, Yamada K, Matsumoto T, Lee KH, Woo JT, Uemura D.
  • Journal Title: J Am Chem Soc. 126 Pages: 4794-4795
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The calcineurin/NFAT signaling pathway regulates osteoclastogenesis in RAW264.7 cells. (2004)
  • Author(s): Hirotani H., Tuohy N.A., Woo J.T., Stern P.H., Clipstone N.A.
  • Journal Title: J Biol Chem. 279 Pages: 13984-13992
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Quercetin suppresses bone resorption by inhibiting the differentiation and activation of osteoclasts. (2004)
  • Author(s): Woo, J.-T., Nakagawa, H., Notoya, M., Yonezawa, T., Udagawa, N., Lee, L.-S., Ohnishi, M., Hagiwara, H., Nagai, K.
  • Journal Title: Biol. Pharm. Bull 27 Pages: 504-509
  • NAID: 110003608794
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Generation of hydrogen peroxide primarily contributes to the induction of Fe(II)-dependent apoptosis in Jurkat cells by (-)- epigallocatechin gallate (2004)
  • Author(s): Nakagawa H, Hasumi K, Woo JT, Nagai K, Wachi M.
  • Journal Title: Carcinogenesis 25 Pages: 1567-1574
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cyclosporine A and FK506 induce osteoclast apoptosis in mouse bone marrow culture (2004)
  • Author(s): Igarashi K, Hirotani H, Woo JT, Stern PH.
  • Journal Title: Bone 35 Pages: 47-56
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Quercetin suppresses bone resorption by inhibiting differentiation and activation of osteoclasts. (2004)
  • Author(s): J-T Woo, H Nakagawa, M Notoya, T Yonezawa, M Ohnishi, K.Nagai
  • Journal Title: Biological Pharm.Bull 27 Pages: 504-509
  • NAID: 110003608794
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The calcineurin/NFAT signaling pathway regulates osteoclastogenesis in RAW264.7 cells. (2004)
  • Author(s): Hirotani H, Tuohy NA, Woo JT, Stern PH, Clipstone NA
  • Journal Title: J Biol Chem. 279 Pages: 13984-13992
• [Journal Article] Symbioimine Exhibiting Inhibitory Effect of Osteoclast Differentiation, from the Symbiotic Marine Dinoflagellate Symbiodinium sp. (2004)
  • Author(s): Kita M, Kondo M, Koyama T, Yamada K, Matsumoto T, Lee KH, Woo JT, Uemura
  • Journal Title: J Am Chem Soc.126 126 Pages: 4794-4795
• [Journal Article] Cyclosporine A and FK506 induce osteoclast apoptosis in mouse bone marrow cell cultures (2004)
  • Author(s): Igarashi K, Hirotani H, Woo JT, Stern PH.
  • Journal Title: Bone 35 Pages: 47-56
• [Journal Article] Generation of hydrogen peroxide primarily contributes to the induction of Fe(II)-dependent apoptosis in Jurkat cells by (-)-epigallocatechin (2004)
  • Author(s): Nakagawa H, Hasumi K, Woo JT, Nagai K, Wachi M.
  • Journal Title: Carcinogenesis 25 Pages: 1567-1574
• [Journal Article] Furosin, an ellagitannin, suppresses RANKL-induced osteoclast differentiation and function through inhibition of MAP kinase activation and actin ring formation (2004)
  • Author(s): Park EK, Kim MS, Lee SH, Kim KH, Park JY, Kim TH, Lee IS, Woo JT, Jung JC
  • Journal Title: Biochem Biophys Res Commun. 325 Pages: 1472-1480