title: Statin-induced Ras activation integrates the phosphatidylinositol 3-kinase signal to Akt and MAPK for bone morphogenetic protein-2 expression in osteoblast differentiation.
abstract: Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.
authors.affiliation: Departments of South Texas Veterans Health Care System, San Antonio, Texas 78229; Geriatric Research, Education, and Clinical Center, and the South Texas Veterans Health Care System, San Antonio, Texas 78229. Electronic address: choudhury@uthscsa.edu.
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.affiliation: Departments of South Texas Veterans Health Care System, San Antonio, Texas 78229; Pathology and South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Chandi Charan
authors.initials: CC
authors.lastname: Mandal
authors.affiliation: Geriatric Research, Education, and Clinical Center, and the South Texas Veterans Health Care System, San Antonio, Texas 78229; Medicine, The University of Texas Health Science Center at San Antonio, the South Texas Veterans Health Care System, San Antonio, Texas 78229; South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000096:biosynthesis; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D011905:Genes, ras / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D000924:Anticholesteremic Agents; D000943:Antigens, Differentiation; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D008148:Lovastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016212:Transforming Growth Factor beta; C525719:Bmp2 protein, mouse; C487757:Pten protein, mouse