2012 Fiscal Year Final Research Report
Molecular mechanism of bone-resorption in osteoclasts through microtubule regulation
| Project/Area Number |
23659707
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TANAKA Sakae 東京大学, 医学部附属病院, 教授 (50282661)
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| Co-Investigator(Kenkyū-buntansha) |
KADONO Yuho 東京大学, 医学部附属病院, 講師 (70401065)
YASUI Tetsuro 東京大学, 医学部附属病院, 助教 (30583108)
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| Project Period (FY) |
2011 – 2012
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| Keywords | 骨 / 軟骨代謝学 |
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| Research Abstract |
We investigated the role of Akt, a downstream effector of phosphatidylinositol 3-kinase, in bone-resorbing activity of mature osteoclasts. Treatment with a specific Akt inhibitor disrupted sealing zone formation and decreased the bone-resorbing activity of osteoclasts. The normal microtubule structures were lost and the Akt inhibitor reduced the amount of acetylated tubulin, which reflects stabilized microtubules, whereas forced Akt activation by adenovirus vectors resulted in the opposite effect. Forced Akt activation increased the binding of themicrotubule-associated protein APC, the APC-binding protein end-binding protein 1 (EB1) and dynactin, a dynein activator complex, with microtubules. Depletion of Akt1 and Akt2 resulted in a disconnection of APC/EB1 and a decrease in bone-resorbing activity along with reduced sealing zone formation, both of which were recovered upon the addition ofLiCl, a GSK-3ss inhibitor. The Akt1 and Akt2 double knock-out mice exhibitedosteosclerosis due to reduced bone resorption. These findings indicate that Akt controls the bone-resorbing activity of osteoclasts by stabilizing microtubules via a regulationof the binding of microtubule associated proteins.
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