2004 Fiscal Year Final Research Report Summary
Comprehensive approach to identify novel molecules involved in osteogenesis and chondrogenesis during tooth development.
| Project/Area Number |
14370596
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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 | Nagasaki University |
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Principal Investigator |
TSUKAZAKI Tomoo Nagasaki University, Graduate School of Biomedical Science, Associated Prof., 大学院・医歯薬学総合研究科, 助教授 (50315230)
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| Co-Investigator(Kenkyū-buntansha) |
FUJITA Syuichi Nagasaki University, Graduate School of Biomedical Science, Assistant Prof., 大学院・医歯薬学総合研究科, 助手 (00181355)
SHIBATA Yasuaki Nagasaki University, Graduate School of Biomedical Science, Assistant Prof., 大学院・医歯薬学総合研究科, 助手 (80253673)
NEMOTO Takayuki Nagasaki University, Graduate School of Biomedical Science, Professor, 大学院・医歯薬学総合研究科, 教授 (90164665)
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| Project Period (FY) |
2002 – 2004
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| Keywords | tooth development / Notch / osteoblast |
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| Research Abstract |
We have investigated to identify novel molecules involved in osteogenesis and chondrogenesis during tooth development by comprehensive approach, including gene chip, proteomics and differential display analysis. From gene chip, we identified that Notch signaling system was up-regulated during tooth development. Functional involvement of the Notch pathway in osteoblastic differentiation has been previously investigated using the truncated intracellular domain, which mimics Notch signaling by interacting with the DNA binding protein CBF-1. However, it is unclear whether Notch ligands Delta1 and Jagged1 also induce an identical cellular response in osteoblastic differentiation. We have shown that both Delta1 and Jagged1 were expressed concomitantly with Notch1 in maturating osteoblastic cells during bone regeneration and that overexpressed and immobilized recombinant Delta1 and Jagged1 alone did not alter the differentiated state of MC3T3-E1 and C2C12 cells but augmented bone morphogeneti
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c protein-2(BMP2)-induced alkaline phosphatase(ALP) activity and the expression of several differentiation markers, except for osteocalcin, and ultimately enhanced calcified nodule and in vivo ectopic bone formation of MC3T3-E1. In addition, both ligands transmitted signal through the CBF-1-dependent pathway and stimulated the expression of HES-1,a direct target of Notch pathway. To study the requistric role of Notch signaling in BMP2-induced differentiation, Notch signaling was inhibited by the dominant negative extracellular domain of Notch1, specific inhibitor, or siRNA. These treatments decreased ALP activity as well as the expression of other differentiation markers and inhibited the promoter activity of Id-1,a target gene of the BMP pathway. These results indicate the functional redundancy between Delta1 and Jagged1 in osteoblastic differentiation, whereby Delta1/Jagged1-activated Notchl enhances BMP2-induced differentiation through the identical signaling pathway. Furthermore, our data also suggest that functional Notch signaling is essential not only for BMP2-induced osteoblast differentiation but also for BMP signaling itself. Less
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