| Project/Area Number |
17390420
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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 |
Orthopaedic surgery
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| Research Institution | Keio University |
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Principal Investigator |
MATSUO Koichi Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (40229422)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGUCHI Toru Keio University, School of Medicine, Instructor, 医学部, 助手 (50338092)
TAKADA Yasunari Keio University, School of Medicine, Instructor, 医学部, 助手 (40407086)
TOYAMA Yoshiaki Keio University, School of Medicine, Professor, 医学部, 教授 (40129549)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,600,000 (Direct Cost: ¥15,600,000)
Fiscal Year 2006: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2005: ¥9,600,000 (Direct Cost: ¥9,600,000)
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| Keywords | Osteoimmunology / Bone remodeling / ephrin / c-Fos / Osteoclast / cytokine / OPG / Auditory ossicles |
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| Research Abstract |
1. Bone homeostasis requires a delicate balance between the activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Various molecules coordinate osteoclast function with that of osteoblasts; however, molecules that mediate osteoclast-osteoblast interactions by simultaneous signal transduction in both cell types have not yet been identified. Here we show that osteoclasts express the NFATc 1 target gene ephrinB2, while osteoblasts express the receptor EphB4, along with other ephrin-Eph family members. Using gain-and loss-of-function experiments, we demonstrate that reverse signaling through ephrinB2 into osteoclast precursors suppresses osteoclast differentiation by inhibiting the osteoclastogenic c-Fos-NFATc 1 cascade. In addition, forward signaling through EphB4 into osteoblasts enhances osteogenic differentiation, and overexpression of EphB4 in osteoblasts increases bone mass in transgenic mice. These data demonstrate that ephrin-Eph bidirectional signaling links two major molecular mechanisms for cell differentiation-one in osteoclasts and the other in osteoblasts-thereby maintaining bone homeostasis (Zhao et al., 2006).
2. Fral transgenic (Tg) mice develop osteosclerosis and exhibit altered expression of bone matrix proteins. We found that expression of Thbsl and Thbs2 was reduced in Fral Tg osteoblasts. Fral Tg and non-osteosclerotic Thbsl-/-Thbs2-/-mice share an edge-to-edge bite. Therefore, reduced expression of thrombospondins may contribute to craniofacial dysmorphism independently of osteosclerosis (Nishiwaki et al., 2006). We also observed that inflammatory cytokine production is reduced in Fral Tg mice and initiation of osteoblastic differentiation is delayed after bone fracture (manuscript in preparation).
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