RRC ID 41845
Author Gingery A, Bradley E, Shaw A, Oursler MJ.
Title Phosphatidylinositol 3-kinase coordinately activates the MEK/ERK and AKT/NFkappaB pathways to maintain osteoclast survival.
Journal J Cell Biochem
Abstract We have examined highly purified osteoclasts that were generated in vitro from murine co-culture of marrow precursors with stromal support cells and have found evidence of activation of the MEK/ERK and AKT/NFkappaB survival pathways. Many mature marrow-derived osteoclasts survived for at least 48 h in culture whether or not they are maintained with stromal cells. Moreover, supplementing purified osteoclasts with RANKL and/or M-CSF had no impact on their survival pattern. In addition, spleen-derived osteoclasts generated with RANKL and M-CSF treatment exhibited a similar survival pattern. Blocking MEK, AKT, or NFkappaB activity resulted in apoptosis of many, but not all, of the osteoclasts in purified marrow-derived osteoclasts, marrow-derived osteoclasts co-cultured with stromal cells, and spleen-derived osteoclasts maintained with RANKL and M-CSF. These data support that both the MEK/ERK and AKT/NFkappaB pathways contribute to osteoclast survival. Since PI3K has been shown to activate either of these pathways, we have examined its role in osteoclast survival. PI3K inhibition caused apoptosis of nearly all osteoclasts in purified and co-cultured marrow-derived osteoclasts and spleen-derived osteoclasts maintained with RANKL and M-CSF. Interestingly, in marrow-derived co-cultures, the apoptotic response was restricted to osteoclasts as there was no evidence of stromal support cell apoptosis. PI3K inhibition also blocked MEK1/2, ERK1/2, and AKT phosphorylation and NFkappaB activation in purified osteoclasts. Simultaneous blockage of both AKT and MEK1/2 caused rapid apoptosis of nearly all osteoclasts, mimicking the response to PI3K inhibition. These data reveal that PI3K coordinately activates two distinct survival pathways that are both important in osteoclast survival.
Volume 89(1)
Pages 165-79
Published 2003-5-1
DOI 10.1002/jcb.10503
PMID 12682917
MeSH Animals Apoptosis Cell Survival Cells, Cultured Coculture Techniques MAP Kinase Signaling System* Mice Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases / metabolism Mitogen-Activated Protein Kinases / metabolism NF-kappa B / metabolism Osteoclasts / cytology Osteoclasts / metabolism* Phosphatidylinositol 3-Kinases / metabolism* Phosphoinositide-3 Kinase Inhibitors Protein-Serine-Threonine Kinases* Proto-Oncogene Proteins / antagonists & inhibitors Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-akt
IF 3.448
Times Cited 133
Human and Animal Cells