2007 Fiscal Year Final Research Report Summary
The relationship between cell proliferation and RANKL-induced osteoclastogenesis
| Project/Area Number |
18390495
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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 |
Functional basic dentistry
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| Research Institution | Matsumoto Dental University |
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Principal Investigator |
TAKAHASHI Naoyuki Matsumoto Dental University, Graduate School of Oral Science, Hard Tissue Research, Professor (90119222)
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| Co-Investigator(Kenkyū-buntansha) |
MIZOGUCHI Toshihide Matsumoto Dental University, Institute for Oral Science, Lecturer (90329475)
KOIDE Masanori Matsumoto Dental University, Institute for Oral Science, Lecturer (10367617)
NAKAMURA Akihiro Matsumoto Dental University, Second Department of Anatomy, Professor (50227930)
NINOMIYA Tadshi Matsumoto Dental University, Institute for Oral Science, Assistant Professor (00360222)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Osteoclasts / RANKL / M-CSF / Osteoblasts / Cell cycle-arrested quiescent osteoclast precursor / OPG / Osteoclast niche / Fos deficient mice |
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| Research Abstract |
(1) In vitro analysis of the cell cycle in osteoclast progenitors : We have shown that cell cycle progression and withdrawal after the progression in osteoclast precursors are the two sequential events essential for RANKL-induced osteoclastogenesis.
(2) The isolation and the analysis of QOPs: Cell cycle-arrested quiescent osteoclast precursors (QOPs) were identified as the committed osteoclast precursors in vitro. In vivo experiments showed that mononuclear cells expressing c-Fms and RANK but not Ki67 were detected along bone surfaces in the vicinity of osteoblasts in RANKL-deficient mice. They were identified as QOPs.
(3) BMP transplantation experiments using RANKL(-/-) mice and OPG(-/-) mice : We examined the requirements for osteoclastogenesis using OPG(-/-) mice, RANKL(-/-) mice and a system involving BMP-induced ectopic bone formation. We have shown that osteoblasts also play important roles in osteoclastogenesis through offering the critical microenvironment for the action of RANKL.
(4) Establishment of the Cre-lox P system for osteoclast specific deletion of target genes : We have succeeded to establish RANK Cre mice. We are now analyzing the Cre recombinase expression in osteoclastss.
(5) Transgenic mice of cell cycle regulatory genes : We are advancing experiments on osteoclast niche, in stead of the production of the cycle regulatory gene transgenic mice.
(6) Clinical application of anti-cancer drugs in bone diseases : We have shown that that taxanes have beneficial effects on the treatment of bone metastatic cancers. Administration of an anti-cancer drug, 5-fluorouracil, to mice induced myelosuppression, but QOPs survived and differentiated into osteoclasts in response to an active vitamin D_3 analog given to those mice. We have shown that QOPs pre-exist at the site of osteoclastogenesis and that osteoblasts play roles in the maintenance of QuOPs in the undifferentiated state. We found that c-Fos(-/-) mice have not osteoclast niche.
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