Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells.
Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. The present study was undertaken to understand the events of osteoblast differentiation induced by statins. Simvastatin at 10(-7) M markedly increased mRNA expression for bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), alkaline phosphatase, type I collagen, bone sialoprotein, and osteocalcin (OCN) in nontransformed osteoblastic cells (MC3T3-E1), while suppressing gene expression for collagenase-1, and collagenase-3. Extracellular accumulation of proteins such as VEGF, OCN, collagenase-digestive proteins, and noncollagenous proteins was increased in the cells treated with 10(-7) M simvastatin, or 10(-8) M cerivastatin. In the culture of MC3T3-E1 cells, statins stimulated mineralization; pretreating MC3T3-E1 cells with mevalonate, or geranylgeranyl pyrophosphate (a mevalonate metabolite) abolished statin-induced mineralization. Statins stimulate osteoblast differentiation in vitro, and may hold promise drugs for the treatment of osteoporosis in the future.
Maeda
Toyonobu
T
Department of Biochemistry, School of Dentistry, Ohu University, Koriyama 963-8611, Japan.
Matsunuma
Ayako
A
Kurahashi
Izuru
I
Yanagawa
Toru
T
Yoshida
Hiroshi
H
Horiuchi
Noboru
N
D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D003094:Collagen / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D058574:Integrin-Binding Sialoprotein; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015675:Osteocalcin / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D015675:Osteocalcin; D003094:Collagen; D000469:Alkaline Phosphatase