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: Takumi Matsumoto, Yuichi Nagase, Jun Hirose, Naoto Tokuyama, Tetsuro Yasui, Yuho Kadono, Kohjiro Ueki, Takashi Kadowaki, Kozo Nakamura, Sakae Tanaka
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 28 Issue 5 Pg. 1191-202 (May 2013) ISSN: 1523-4681 [Electronic] United States
• PMID: 23239117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Bone and Mineral Research.

Chemical References

• Tubulin
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Animals
• Bone Resorption
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microtubules (metabolism)
• Osteoclasts (metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-akt (metabolism)
• Tubulin (metabolism)