| Project/Area Number |
15380077
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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 |
Applied biochemistry
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| Research Institution | Chubu University |
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Principal Investigator |
NAGAI Kazuo Chubu University, College of Bioscience and Biotechnology, Professor, 応用生物学部, 教授 (00011974)
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| Co-Investigator(Kenkyū-buntansha) |
WOO Je-tae Chubu University, College of Bioscience and Biotechnology, Professor, 応用生物学部, 教授 (20272693)
OHNISHI Motoko Chubu University, College of Bioscience and Biotechnology, Assistant Professor, 応用生物学部, 助教授 (00312653)
MINAMI Motoyasu Chubu University, College of Bioscience and Biotechnology, Assistant Professor, 応用生物学部, 助教授 (90340207)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2004: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2003: ¥9,900,000 (Direct Cost: ¥9,900,000)
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| Keywords | destruxins / reveromycin A / mevastatin / bone resorption / osteoclast / osteoporosis / cell death / inhibition / 骨吸収抑制剤 / アポトーシス / タンパク質合成 / 微生物代謝産物 / tRNA / 酸性環境 / 選択作用 |
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| Research Abstract |
In the course of screening for natural compounds that prevent or cure osteoporosis, we found reveromycin A (RMA), mevastatin, destruxins, which are targeted to the function and survival of mature osteoclats. In the present study, we determined the effects of these three compounds on osteoclastic bone resorption in vitro and in vivo. The effect of RM-A was decreased by disruption of the acidic microenvironment in activated osteoclasts, and increased in acidic culture condition. 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 cells such as RAW 264 cells or M-CSF-dependent bone marrow cells in the presence of RANKL. The inhibitory effects of mevastatin were overcome by the addition of mevalonate, farnesyl pyrophosphate or geranylgeranyl pyrophosphate. Geranylgeranyl transferase inhibitor, but not farnesyl transferase inhibitor, inhibited early differentiation of osteoclasts induced by RANKL, suggesting that the geranylgeranylation of these proteins is involved in the inhibitory effect of mevastatin on early differentiation of osteoclasts. Cyclodepsipeptides, destruxin B and E, were found to inhibit osteoclastic bone resorption without affecting osteoclast differentiation and survival, but destruxin E did not inhibit the increase of bone resorption in ovariectomised mice.
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