title: Regulation of bone resorption and sealing zone formation in osteoclasts occurs through protein kinase B-mediated microtubule stabilization.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nagase
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.forename: Naoto
authors.initials: N
authors.lastname: Tokuyama
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yasui
authors.forename: Yuho
authors.initials: Y
authors.lastname: Kadono
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001862:Bone Resorption; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D014404:Tubulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3