Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B-mediated vesicle transport

• Published in: Journal of bone and mineral research Vol. 27; no. 12; pp. 2464 - 2475
• Main Authors: Shinohara, Masahiro, Nakamura, Masaki, Masuda, Hironari, Hirose, Jun, Kadono, Yuho, Iwasawa, Mitsuyasu, Nagase, Yuuichi, Ueki, Kohjiro, Kadowaki, Takashi, Sasaki, Takehiko, Kato, Shigeaki, Nakamura, Hiroaki, Tanaka, Sakae, Takayanagi, Hiroshi
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2012; Wiley; Oxford University Press
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Biological and medical sciences; Bone diseases; BONE RESORPTION; Bone Resorption - physiopathology; Cell activation; Class Ia Phosphatidylinositol 3-Kinase - physiology; CLASS IA PI3K; CONDITIONAL KNOCKOUT MOUSE; Fundamental and applied biological sciences. Psychology; Growth factor receptors; Integrins; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - pharmacology; Mice; Mice, Knockout; Mice, Transgenic; OSTEOCLAST; Osteoclasts; Osteoclasts - physiology; Osteopetrosis - pathology; Phosphatidylinositol Phosphates - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Regulatory subunits; Skeleton and joints; Vertebrates: osteoarticular system, musculoskeletal system; VESICLE TRANSPORT; Vesicles; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Biological transport; Rodentia; Resorption; CLASS IA PI3K; Osteoclast; Osteoarticular system; Phosphatidylinositol; Vertebrata; Mammalia; Mouse; CONDITIONAL KNOCKOUT MOUSE; Kinase; BONE RESORPTION; VESICLE TRANSPORT; Mutation; Bone
• ISSN: 0884-0431; 1523-4681; 1523-4681
• DOI: 10.1002/jbmr.1703

Class IA phosphatidylinositol 3‐kinases (PI3Ks) are activated by growth factor receptors and regulate a wide range of cellular processes. In osteoclasts, they are activated downstream of αvβ3 integrin and colony‐stimulating factor‐1 receptor (c‐Fms), which are involved in the regulation of bone‐resorbing activity. The physiological relevance of the in vitro studies using PI3K inhibitors has been of limited value, because they inhibit all classes of PI3K. Here, we show that the osteoclast‐specific deletion of the p85 genes encoding the regulatory subunit of the class IA PI3K results in an osteopetrotic phenotype caused by a defect in the bone‐resorbing activity of osteoclasts. Class IA PI3K is required for the ruffled border formation and vesicular transport, but not for the formation of the sealing zone. p85α/β doubly deficient osteoclasts had a defect in macrophage colony‐stimulating factor (M‐CSF)–induced protein kinase B (Akt) activation and the introduction of constitutively active Akt recovered the bone‐resorbing activity. Thus, the class IA PI3K‐Akt pathway regulates the cellular machinery crucial for osteoclastic bone resorption, and may provide a molecular basis for therapeutic strategies against bone diseases. © 2013 American Society for Bone and Mineral Research.