| Project/Area Number |
12470393
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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 (2001)
Showa University (2000) |
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Principal Investigator |
TAKAHASHI Naoyuki Institute for Dental Science, Professor, 総合歯科医学研究所, 教授 (90119222)
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| Co-Investigator(Kenkyū-buntansha) |
MIZOGUCHI Toshihide Dental Material, Research Assistant, 総合歯科医学研究所, 助手 (90329475)
HIRAOKA Yukihiro Biochemistry, Associate Professor, 歯学部, 助教授 (20097512)
UDAGAWA Nobuyuki Biochemistry, Professor, 歯学部, 教授 (70245801)
SASAKI Takahisa Department of Oral Histology, School of Dentistry, Showa University, 医学部, 教授 (50129839)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥16,500,000 (Direct Cost: ¥16,500,000)
Fiscal Year 2001: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2000: ¥11,800,000 (Direct Cost: ¥11,800,000)
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| Keywords | Osteoclasts / Macrophage / Osteoblast / Inflammatory cytokine / p38 MAP kinase / Lipopolysaccharide / ERK / RANKL |
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| Research Abstract |
The mechanism of osteoclastogenesis induced by lipopolysaccharide (LPS) was studied in cocultures of mouse osteoblasts and bone marrow cells. LPS stimulated osteoclastogenesis and prostaglandin E_2 (PGE_2) production in the cocultures, both of which were inhibited by NS398, a cyclooxygenase-2 inhibitor. LPS stimulated receptor activator of NF-κB ligand (RANKL) mRNA expression, and inhibited osteoprotegerin (OPG) mRNA expression in osteoblasts. NS398 inhibited only LPS-induced down-regulation of OPG mRNA expression, suggesting that LPS-stimulated PGE_2 production is important for the down-regulation of OPG. Indeed, NS398 failed to inhibit LPS-induced osteoclastogenesis in cocultures containing OPG knockout mouse-derived osteoblasts. Calcium/protein kinase C (PKC) inhibitors and PD98059 [mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor] suppressed RANKL mRNA expression in osteoblasts, and inhibited osteoclastogenesis in the cocultures treated with LPS. LPS induced phosphorylation of MEK and ERK in osteoblasts, and this induction was inhibited by calcium/PKC inhibitors. In addition, PD98059 and NS398 inhibited interleukin 1 (IL-1)-induced osteoclastogenesis in the cocultures, but only PD98059 suppressed RANKL mRNA expression induced by IL-1 in osteoblasts. These results suggest that LPS and IL-1 similarly promote osteoclastogenesis through two parallel events : enhancement of RANKL expression through calcium/PKC signals followed by MEK/ERK signals, and suppression of OPG production mediated by PGE_2.
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