title: Simvastatin promotes osteoblast viability and differentiation via Ras/Smad/Erk/BMP-2 signaling pathway.
abstract: Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a rate-limiting step in cholesterol synthesis. Statins are able to reduce cardiovascular risk in hypercholesterolemic patients. In recent years, the possible effect of statins on bone tissue has received particular attention. The present study was undertaken to understand the events of osteoblast differentiation induced by statins. Our hypothesis is that simvastatin promotes osteoblast viability and differentiation via Ras/Smad/Erk/bone morphogenic protein (BMP)-2 signaling pathway. The viability and differentiation of osteoblasts were examined by mitochondrial activity assay, alkaline phosphatase (ALP) activity, and gene expression. The associated signaling pathways were analyzed by cytoplasmic and membrane proteins manifestation. After administration of 10(-6) M simvastatin, the ALP activity was significantly enhanced, and the expression of BMP-2, ALP, sialoprotein, and type I collagen genes were up-regulated. After simvastatin treatment, both the RasGRF1 and phospho-RasGRF1 in the cytoplasm decreased significantly, whereas those on the plasma membrane increased. A marked increase in membranous GAP-associated protein (P190) and the activated form of both phospho-extracellular signal-regulated kinase1/2 and phospho-Smad1 were also noted. In conclusion, this study shows that statins pose a positive effect on the metabolism of osteoblasts. Simvastatin can promote osteoblast viability and differentiation via membrane-bound Ras/Smad/Erk/BMP-2 pathway. Statins stimulate osteoblast differentiation in vitro and may be a promising drug for the treatment of osteoporosis in the future.
authors.affiliation: Graduate Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
authors.forename: Jui-Sheng
authors.initials: JS
authors.lastname: Sun
authors.forename: Yang-Hwei
authors.initials: YH
authors.lastname: Tsuang
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Chen
authors.forename: Pei-Wei
authors.initials: PW
authors.lastname: Weng
authors.forename: Feng-Huei
authors.initials: FH
authors.lastname: Lin
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D051785:Smad Proteins / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D018631:ras Proteins / Q000502:physiology*
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D024042:Collagen Type I; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D051785:Smad Proteins; D019821:Simvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D000469:Alkaline Phosphatase; D018631:ras Proteins