Molecular and tissue responses in the healing of rat calvarial defects after local application of simvastatin combined with alpha tricalcium phosphate

• Published in: Journal of biomedical materials research. Part B, Applied biomaterials Vol. 93B; no. 1; pp. 65 - 73
• Main Authors: Nyan, Myat, Miyahara, Takayuki, Noritake, Kanako, Hao, Jia, Rodriguez, Reena, Kuroda, Shinji, Kasugai, Shohei
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2010
• Subjects: alpha tricalcium phosphate; Animals; Base Sequence; Biocompatible Materials - administration & dosage; BMP-2; bone formation; bone healing; Bone Morphogenetic Protein 2 - genetics; Bone Regeneration - drug effects; Bone Regeneration - genetics; Bone Regeneration - physiology; Calcium Phosphates - administration & dosage; Cell Movement - drug effects; Cell Proliferation - drug effects; Delayed-Action Preparations; DNA Primers - genetics; Drug Delivery Systems; Gene Expression Profiling; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Male; Materials Testing; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - physiology; Rats; Rats, Wistar; RNA, Messenger - genetics; RNA, Messenger - metabolism; simvastatin; Simvastatin - administration & dosage; Skull - cytology; Skull - drug effects; Skull - injuries; Skull - physiology; TGF-β; Time Factors; Tissue Engineering; Transforming Growth Factor beta1 - genetics; Up-Regulation - drug effects
• ISSN: 1552-4973; 1552-4981; 1552-4981
• DOI: 10.1002/jbm.b.31559

We have previously reported that healing of rat calvarial defects was enhanced by application of alpha tricalcium phosphate (αTCP) 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 αTCP 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‐β1 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‐β1 and BMP‐2, which were stimulated by simvastatin. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2010