Phosphatidylinositol 3 kinase/Akt signal relay cooperates with smad in bone morphogenetic protein-2-induced colony stimulating factor-1 (CSF-1) expression and osteoclast differentiation.
Murine spleen cells produce mature osteoclasts when cocultured with osteoblastic cells. Colony-stimulating factor (CSF)-1 is the growth factor required for differentiating the monocyte-macrophage precursor cells into preosteoclasts. Bone morphogenic protein (BMP) signaling in osteoblasts regulates bone mass in mice, suggesting a role of BMP in osteoclastogenesis along with osteoblast activity. The intracellular signal transduction cross talk regulating the osteoblastic production of CSF-1 as a mechanism of BMP-induced osteoclastogenesis is described in this report. We have recently described the involvement of Smad 1/5 in BMP-2-induced CSF-1 expression and osteoclast formation. In this study, using the pharmacological inhibitors and the adenovirus (Ad) vectors expressing dominant-negative (DN) phosphatidylinositol 3 kinase (PI3K), the PI3K-signaling inhibitor, phosphatase and tensin homolog deleted in chromosome 10 (PTEN) or DN Akt kinase in the in vitro coculture assay, we show an essential role of the lipid kinase cascade in BMP-2-mediated multinucleated osteoclast formation and CSF-1 mRNA expression, transcription, and secretion. Inhibition of PI3K/Akt signaling blocked the binding of Smads 1/5 to the CSF-1 BMP-responsive element present in the CSF-1 promoter, resulting in attenuation of Smad-dependent CSF-1 transcription. Furthermore, PI3K inhibition and DN Akt prevented association of the transcriptional coactivator, CREB (cAMP response element binding protein) binding protein (CBP), with Smads 1/5. Together, these data for the first time demonstrate that PI3K-dependent Akt activation regulates BMP-2-induced CSF-1 expression and provides a mechanism for osteoblastic cell-assisted osteoclast differentiation.
Mandal
Chandi C
CC
Department of Pathology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Ghosh Choudhury
Goutam
G
Ghosh-Choudhury
Nandini
N
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D015870:Gene Expression; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism
D055396:Bone Morphogenetic Protein 2; D051898:Smad1 Protein; D051902:Smad5 Protein; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt