Molecular and tissue responses in the healing of rat calvarial defects after local application of simvastatin combined with alpha tricalcium phosphate.
We have previously reported that healing of rat calvarial defects was enhanced by application of alpha tricalcium phosphate (alphaTCP) combined with simvastatin, a cholesterol synthesis inhibitor. The purpose of the present study was to investigate the cellular and molecular mechanisms in this phenomenon. Rat calvarial defects were grafted with alphaTCP with or without simvastatin or left untreated. Animals were sacrificed on 3, 7, 10, 14, and 21 days postoperatively and histological changes in the defect region were assessed. Gene expression patterns were examined by RT-PCR. Proliferation and migration of osteoprogenitor cells from the dura mater were increased in simvastatin group from day 3 to day 10 (p < 0.01). New bone formation was significantly increased in simvastatin group on day 14 and day 21 (p < 0.01). BMP-2 expression was significantly higher in simvastatin group on day 3 and day 14 (p < 0.05) and maintained until day 21. Increased upregulation of TGF-beta1 was also observed in the simvastatin group on day 7 (p < 0.05) which was maintained until day 14. These findings suggest that the proliferation and recruitment of osteoprogenitor cells were critical steps in early stage of bone healing and that these steps were enhanced by TGF-beta1 and BMP-2, which were stimulated by simvastatin.
Nyan
Myat
M
Department of Oral Implantology and Regenerative Dental Medicine, Tokyo Medical and Dental University, Tokyo, Japan. myatnyan@gmail.com
Miyahara
Takayuki
T
Noritake
Kanako
K
Hao
Jia
J
Rodriguez
Reena
R
Kuroda
Shinji
S
Kasugai
Shohei
S
D000818:Animals; D001483:Base Sequence; D001672:Biocompatible Materials / Q000008:administration & dosage; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D001861:Bone Regeneration / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D002130:Calcium Phosphates / Q000008:administration & dosage*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D020869:Gene Expression Profiling; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D008422:Materials Testing; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage*; D012886:Skull / Q000166:cytology / Q000187:drug effects* / Q000293:injuries / Q000502:physiology*; D013997:Time Factors; D023822:Tissue Engineering; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D001672:Biocompatible Materials; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D002130:Calcium Phosphates; D017931:DNA Primers; D003692:Delayed-Action Preparations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C485828:alpha-tricalcium phosphate; D019821:Simvastatin