| Project/Area Number |
16591482
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Hokkaido University (2005)
Gifu University (2004) |
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Principal Investigator |
ISHISAKI Akira Hokkaido University, Graduate School of Dentistry, Associate Professor, 大学院・歯学研究科, 助教授 (20356439)
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| Co-Investigator(Kenkyū-buntansha) |
KOZAWA Osamu Gifu University, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (90225417)
MATSUNO Hiroyuki Doshisha Women's College of Liberal Arts, Department of Clinical Pathological Biochemistry, Professor, 薬学部, 教授 (40273148)
NAKAJIMA Keiichi National Agricultural Research Center for Hokkaido, Department of Animal Production and Grassland, Senior Researcher, 畜産草地部, 主任研究官 (70362150)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | osteoblast / osteoclast / fibrinolytic factor / bone metabolism / gene knockout mice / ovariectomy / 線溶系 / 骨髄 / 遺伝子ノックアウトマウス / プラスミン |
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| Research Abstract |
The fibrinolytic system contains a proenzyme, plasminogen, that is converted to the active serine protease plasmin, a main component of the fibrinolytic system, by tissue-type plasminogen activator (tPA) or urokinase-type PA (uPA). Inhibition of the system may occur through neutralization of the plasminogen activators or plasmin. This neutralization is achieved mainly by plasminogen activator inhibitor-1 (PAI-1) or α2-antiplasmin (α2-AP-/-/), respectively. Apart from the removal of fibrin, the detailed mechanism how the system affects bone turnover remains to be clarified.
To elucidate the role of the fibrinolytic system in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of plasminogrn gene (Plg-/-) and α2-AP gene (α2-AP-/-) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (Sham) and compared with wild-type (WT) mice. The WT and Plg-/- mice with OVX showed decreased trabecular bone density. In contrast, no significant change in trabecular bone density was detected in α2-AP-/- mice after OVX. On the other, plasminogen inactivation affected bone metabolism at baseline of trabecular bone density in mice. The baseline of trabecular bone in Plg-/- mice was significantly lower than that in either WT or α2-AP-/- mice. Thus, in conditions of estrogen deficiency, α2-AP inactivation protects against trabecular bone loss. On the contrary, plasminogen inactivation promotes trabecular bone loss. In addition, bone resorption, an assay for osteoclast (OC) activity, was affected by the deficiency of either plasminogen or α2-AP : OC activity from bone marrow (BM) of Plg-1-/- mice was significantly higher than that of WT mice. In contrast, OC activity from BM of α2-AP-/- mice was significantly lower than that of WT mice. Taken together, these data suggest that the fibrinolytic system affects bone turnover by regulating osteoclast activity.
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