2004 Fiscal Year Final Research Report Summary
Signal transduction of RANK and Toll-like receptor in alveolar bone destruction
| Project/Area Number |
15390565
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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 |
UDAGAWA Nobuyuki Matsumoto Dental University, School of Oral Dentistry, Professor, 歯学部, 教授 (70245801)
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| Co-Investigator(Kenkyū-buntansha) |
OZAWA Hidehiro Matsumoto Dental University, Graduate School of Oral Medicine, Professor, 大学院・歯学独立研究科, 教授 (60018413)
OKUMURA Shigeki Matsumoto Dental University, School of Dentistry, Research Assistant, 歯学部, 助手 (80350825)
MIZOGUCHI Toshihide Matsumoto Dental University, Institute of Oral Science, Research Assistant, 総合歯科医学研究所, 助手 (90329475)
HIRAOKA Yukihiro Matsumoto Dental University, Graduate School of Oral Medicine, Professor, 大学院・歯学独立研究科, 教授 (20097512)
FURUSAWA Kiyofumi Matsumoto Dental University, Graduate School of Oral Medicine, Professor, 大学院・歯学独立研究科, 教授 (90165481)
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| Project Period (FY) |
2003 – 2004
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| Keywords | LPS / MyD88 / TRIF / TRAM / IL-1 / IL-6 / bone marrow macrophage / mouse |
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| Research Abstract |
LPS is a potent stimulator of bone resorption in inflammatory diseases caused by bacteria. Bacterial lipoprotein/lipopeptides are also pathogen-specific molecular patterns. Toll-like receptor 4 (TLR4) is identified as the signaling receptor for LPS. The complex of TLR6 and TLR2 recognizes diacyl lipopeptide. The signaling cascade of TLR is similar to that of IL-1 receptors, because both TLR and IL-1receptors use MyD88 as a common signaling molecule. Toll-IL-1 receptor domain-containing adapter inducing interferon-γ (TRIF)-mediated signals are also shown to be involved in LPS-induced MyD88-independent pathway. Using MyD88-deficient (MyD88^<-/->) mice and TRIF-deficient (TRIF^<-/->) mice, we examined roles of MyD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide (DL) and IL-1 stimulated osteoclastogenesis in co-cultures of osteoblasts and hemopoietic cells obtained from TRIF^<-/-> mice but not MyD88^<-/-> mice. Bone marrow hemopoietic cells from MyD88^<-/-> m
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ice and TRIF^<-/-> mice similarly differentiated into osteoclasts in response to RANKL plus M-CSF. LPS, DL and IL-1 stimulated RANKL mRNA expression in TRIF^<-/-> osteoblasts but not MyD88^<-/-> osteoblasts, suggesting that only MyD88-mediated signal in osteoblasts was important for RANKL expression in response to those factors. This finding was particularly interesting, because both MyD88-dependent and TRIF-dependent pathways are essential for LPS-induced cytokine production in macrophages. Indeed, LPS failed to stimulate IL-6 production in TRIF^<-/-> bone marrow macrophages. But, LPS could stimulate IL-6 production in TRIF^<-/-> osteoblasts. LPS and IL-1 enhanced the survival of TRIF^<-/-> osteoclasts but not MyD88^<-/-> osteoclasts. DL did not support the survival of osteoclasts, because of the lack of TLR6 in osteoclasts. TRIF-related adaptor molecule (TRAM) was shown to be essentially involved in the TRIF-mediated signaling pathway. Interestingly, macrophages expressed both TRIF and TRAM mRNAs, while osteoblasts and osteoclasts expressed only TRIF mRNA. The fact that TRIF-mediated signals are not required for LPS-induced RANKL and IL-6 expression in osteoblasts and for osteoclast survival may be related to the lack of TRAM expression in osteoblasts and osteoclasts. Bone histomorphometry showed that MyD88^<-/-> mice exhibited low turnover osteoporosis with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MyD88 is physiologically involved in bone turnover. Less
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