Statin suppresses apoptosis in osteoblastic cells: role of transforming growth factor-beta-Smad3 pathway.
Statins possess pleiotropic effects in several tissues. Among them, their bone anabolic actions have been recently noted. We have proposed that Smad3, a TGF-beta-signaling molecule, is a promoter of bone formation. However, whether statins would affect TGF-beta-Smad3 pathway in osteoblasts is still unknown. The present study was performed to examine the effects of statin on Smad3 expression and cell apoptosis by employing mouse osteoblastic MC3T3-E1 and rat osteoblastic UMR-106 cells. Statins (pitavastatin, mevastatin, and simvastatin) as well as alendronate increased the levels of Smad3 in MC3T3-E1 cells. The effects of pitavastatin on Smad3 levels were observed from 3 hours and later. Pitavastatin induced the expression of TGF-beta, and cycloheximide, a protein synthesis inhibitor, antagonized the increased levels of pitavastatin on Smad3. On the other hand, pitavastatin antagonized dexamethasone- or etoposide-induced apoptosis in a dose-dependent manner, and Smad3 inactivation by dominant negative Smad3 or an inhibition of endogenous TGF-beta action by SB431542 antagonized anti-apoptotic effects of pitavastatin, indicating that pitavastatin suppressed osteoblast apoptosis partly through TGF-beta-Smad3 pathway. In conclusion, the present study has demonstrated for the first time that statin suppressed cell apoptosis partly through TGF-beta-Smad3 pathway in osteoblastic cells.
Kaji
H
H
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. hiroshik@med.kobe-u.ac.jp
Naito
J
J
Inoue
Y
Y
Sowa
H
H
Sugimoto
T
T
Chihara
K
K
D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D051900:Smad3 Protein / Q000032:analysis / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C012258:mevastatin; D008148:Lovastatin; D019821:Simvastatin; C108475:pitavastatin; D019386:Alendronate