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Class IA phosphatidylinositol 3‐kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport
Author(s) -
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
Publication year - 2012
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.1703
Subject(s) - microbiology and biotechnology , bone resorption , phosphatidylinositol , chemistry , protein kinase a , kinase , endocrinology , biology
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 α v β 3 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.