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Regulation of bone resorption and sealing zone formation in osteoclasts occurs through protein kinase b–mediated microtubule stabilization
Author(s) -
Matsumoto Takumi,
Nagase Yuichi,
Hirose Jun,
Tokuyama Naoto,
Yasui Tetsuro,
Kadono Yuho,
Ueki Kohjiro,
Kadowaki Takashi,
Nakamura Kozo,
Tanaka Sakae
Publication year - 2013
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.1844
Subject(s) - microtubule , bone resorption , resorption , microbiology and biotechnology , chemistry , protein kinase a , kinase , medicine , biology
We investigated the role of protein kinase B (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 the microtubule‐associated protein adenomatous polyposis coli (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 of LiCl, a glycogen synthase kinase‐3β (GSK‐3β) inhibitor. The Akt1 and Akt2 double‐knockout mice exhibited osteosclerosis due to reduced bone resorption. These findings indicate that Akt controls the bone‐resorbing activity of osteoclasts by stabilizing microtubules via a regulation of the binding of microtubule associated proteins. © 2013 American Society for Bone and Mineral Research.