Regulation of bone resorption and sealing zone formation in osteoclasts occurs through protein kinase b–mediated microtubule stabilization. (17th April 2013)

• Record Type: Journal Article
• Authors: Matsumoto, Takumi; Nagase, Yuichi; Hirose, Jun; Tokuyama, Naoto; Yasui, Tetsuro; Kadono, Yuho; Ueki, Kohjiro; Kadowaki, Takashi; Nakamura, Kozo; Tanaka, Sakae
• Is Part Of: Journal of bone and mineral research. Volume 28:Number 5(2013:May)
• Page Start: 1191
• Page End: 1202
• Publication Date: 2013-04-17
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.1844
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>Akt1</italic> and <italic>Akt2</italic> 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 <italic>Akt1</italic> and <italic>Akt2</italic> 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.</p> </abstract>