| Project/Area Number |
14370599
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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 Medicine, Hard Tissue Research, Professor, 大学院・歯学独立研究科, 教授 (90119222)
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| Co-Investigator(Kenkyū-buntansha) |
MIZOGUCHI Toshihide Matsumoto Dental University, Institute for Oral Science, Hard Tissue Research, Research Associate, 総合歯科医学研究所, 助手 (90329475)
UDAGAWA Nobuyuki Matsumoto Dental University, School of Dentistry, Biochemistry, Professor, 歯学部, 教授 (70245801)
OZAWA Hidehiro Matsumoto Dental University, Graduate School of Oral medicine, Hard Tissue, Research Professor, 大学院・歯学独立研究科, 教授 (60018413)
TAKAHASHI Masahiro Matsumoto Dental University, School of Dentistry, Maxillofacial Surgery, Research Associate, 歯学部, 助手 (90340059)
KAWAKAMI Toshiyuki Matsumoto Dental University, Graduate School of Oral Medicine, Hard Tissue Research, Professor, 大学院・歯学独立研究科, 教授 (80104892)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2003: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2002: ¥8,300,000 (Direct Cost: ¥8,300,000)
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| Keywords | Lipopolysaccharide (LPS) / IL-1 / osteoclast / MyD88 / Muramyl dipeptide (MDP) / Nod2 / TRIF / PGE_2 receptor / マクロファージ / 骨芽細胞 / インターロイキン1 / 樹状細胞 / RANKL / p38MAPK |
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| Research Abstract |
Aim of the study :
The discovery of RANKL elucidates the mechanism of osteoclast differentiation and function regulated by osteoblasts. Using OPG-deficient (OPG-/-) mice, MyD88-deficient (MyD88-/-) mice, and TRIF-deficient (TRIF-/-) mice, we examined signal transduction and cell-to-cell communication in the bone resorption induced by inflammation PGE_2 has been shown to enhance RANKL-induced differentiation of the precursor cells into osteoclasts. We examined how PGE2 directly enhance differentiation of osteoclast progenitors. The role of PGE_2 receptors in osteoclasts was examined, using an EP4 expression vector.
Results :
(1)LPS stimulated the survival of purified osteoclasts through TLR4 signals. (2)p38MAP kinase was essentially involved in the differentiation of bone marrow macrophages (osteoclast precursors) into osteoclasts. The p38MAP kinase pathway was all dead in mature osteoclasts. (3)Using OPG-/-mice, we showed that IL-1 as well as LPS stimulated osteoclastogenesis through two
… More
parallel events : direct enhancement of RANKL expression and suppression of OPG expression. (4)Using MyD88-deficient (-/-) mice and TRF-/-mice, we showed that MyD88 signals but not TRIF signals were essentially involved in RANKL expression in osteoblasts treated with IL-1 and LPS. MyD88 signals were also essential for the survival of osteoclasts supported by LPS and IL-1. (5)Destruxin, bisphosphonates, and strontium compound S12911-2 inhibit osteoclastic bone resorption. Destruxin was shown to inhibit pit-forming activity of osteoclasts without affecting their differentiation and survival. V-ATPase induced acidification beneath the ruffled borders of osteoclasts triggers the incorporation of bisphosphonates into osteoclasts. S12911-2 was shown to inhibit ruffled border formation in osteoclasts. (6)Muramyl dipeptide (MDP) is the essential structure responsible for the immunoadjuvant activity of peptidoglycan of gram-positive and -negative bacterial walls. MDP synergistically enhanced osteoclast formation induced by LPS, IL-1α and TNF-α through RANKL expression in osteoblasts. Nod2mediated signals appear to be involved in the MDP-induced RANKL expression in osteoblasts. (7) PGE_2 has been shown to enhance RANKL-induced differentiation of the precursor cells into osteoclasts. PGE2 synergistically enhanced osteoclastic differentiation of RAW264.7cells through EP2 and EP4. In contrast, mature osteoclasts did not express functional EP2 or EP4. When EP4 cDNA was transfected into mature osteoclasts, the bone-resorbing activity was markedly inhibited by PGE_2. Less
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