title: Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade.
abstract: SHIP is an SH2-containing inositol-5-phosphatase expressed in hematopoietic cells. It hydrolyzes the PI3K product PI(3,4,5)P(3) and blunts the PI3K-initiated signaling pathway. Although the PI3K/Akt pathway has been shown to be important for osteoclastogenesis, the molecular events involved in osteoclast differentiation have not been revealed. We demonstrate that Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. Inhibition of the PI3K by LY294002 reduces formation of osteoclasts and attenuates the expression of NFATc1, but not that of c-Fos. Conversely, overexpression of Akt in bone marrow-derived macrophages (BMMs) strongly induced NFATc1 expression without affecting c-Fos expression, suggesting that PI3K/Akt-mediated NFATc1 induction is independent of c-Fos during RANKL-induced osteoclastogenesis. In addition, we found that overexpression of Akt enhances formation of an inactive form of GSK3β (phospho-GSK3β) and nuclear localization of NFATc1, and that overexpression of a constitutively active form of GSK3β attenuates osteoclast formation through downregulation of NFATc1. Furthermore, BMMs from SHIP knockout mice show the increased expression levels of phospho-Akt and phospho-GSK3β, as well as the enhanced osteoclastogenesis, compared with wild type. However, overexpression of a constitutively active form of GSK3β attenuates RANKL-induced osteoclast differentiation from SHIP-deficient BMMs. Our data suggest that the PI3K/Akt/GSK3β/NFATc1 signaling axis plays an important role in RANKL-induced osteoclastogenesis.
authors: Chonnam National University Medical School, Gwangju, Korea.
authors: Jang Bae
authors: JB
authors: Moon
authors: Jung Ha
authors: JH
authors: Kim
authors: Kabsun
authors: K
authors: Kim
authors: Bang Ung
authors: BU
authors: Youn
authors: Aeran
authors: A
authors: Ko
authors: Soo Young
authors: SY
authors: Lee
authors: Nacksung
authors: N
authors: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases