Statin-induced Ras activation integrates the phosphatidylinositol 3-kinase signal to Akt and MAPK for bone morphogenetic protein-2 expression in osteoblast differentiation.
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.
Ghosh-Choudhury
Nandini
N
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.
Mandal
Chandi Charan
CC
Departments of South Texas Veterans Health Care System, San Antonio, Texas 78229; Pathology and South Texas Veterans Health Care System, San Antonio, Texas 78229.
Choudhury
Goutam Ghosh
GG
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.
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
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