| Project/Area Number |
11470315
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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 | University of Occupational and Environmental Health |
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Principal Investigator |
SAKAI Akinori University of Occupational and Environmental Health, School of Medicine, Associate Professor, 医学部, 助教授 (90248576)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Toshitaka University of 0ccupational and Environmental Health, School of Medicine, Professor, 医学部, 教授 (50082235)
鶴上 浩 産業医科大学, 医学部, 講師 (70299618)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 2001: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1999: ¥4,400,000 (Direct Cost: ¥4,400,000)
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| Keywords | Unloading / Bone marrow cell / p53 / Mineralization / Apoptosis / Tail-suspension / Knockout mouse / Gene / 骨芽細胞 / p21 / 不動 / 骨粗鬆症 / 破骨細胞 / 副甲状腺ホルモン / RANKL / 形態計測 / マウス |
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| Research Abstract |
Skeletal unloading induces bone loss in loaded bones in humans and animals. We tested the hypothesis that mechanical unloading facilitates signaling of p53, an important modulator of cell cycling and apoptosis, in bone marrow cells, thereby reduces trabecular bone volume. We performed histomorphometric analyses and bone marrow cell cultures in tail-suspended p53 null p53(-/-) and wild-type p53(+/+) mice. Eight-week-old male mice were assigned to four groups as follows, after acclimatization for one week : p53(+/+)+ground control (GC), p53(+/+)+tail-suspension (TS), p53(-/-)+GC, and p53(-/-)+TS. Bilateral tibial samples were used for analysis. The histomorphometric parameters of trabecular structure, formation and resorption did not differ between the p53(+/+)+GC and p53(+/+)+GC groups. Trabecular bone volume in p53(+/+)+TS mice was significantly reduced to 45% of that in the p53(+/+)+GC group after one week of TS. In contrast, bone volume in p53(-/-)+TS mice was preserved at the same l
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evel as that in the p53(-/-)+GC group. The bone formation rate was significantly reduced in p53(+/+)+TS but not in p53(-/-)+TS mice. In bone marrow cell culture, the numbers of alkaline phosphatase (ALP)-positive colony-forming units-fibroblastic (CFU-f) and mineralized nodules were significantly reduced in p53(+/+)+TS, but not p53(-/-)+TS mice. Flow cytometric cell cycle analysis revealed that unloading significantly increased the percentage of hypoploid bone marrow cells in p53(+/+) mice relative to that in p53(+/+)+GG mice, but there was no significant difference in ploidy between p53(-/-)+TS and p53(-/-)+GC mice. p53 and p21 mRNA expression was enhanced after TS in bone marrow cells from p53(+/+) mice. Our data demonstrate that trabecular bone mass and bone formation were preserved after TS in p53(-/-) mice, closely associated with ALP-positive CFU-f and mineralized nodule formation in marrow cultures obtained from tibiae of p53(-/-) mice. We speculate that bone loss due to mechanical unloading may be related to facilitation of intracellular p53-p21 signaling. Less
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