title: Calvarial defect healing by recruitment of autogenous osteogenic stem cells using locally applied simvastatin.
abstract: Local statins implant has been shown to promote bone healing, the underlying mechanisms are unclear. The purpose of this study was to test the effect of local simvastatin implant on bone defect healing; to evaluate the mobilization, migration, and homing of bone marrow-derived mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs) induced by simvastatin. We found that local simvastatin implant increased bone formation by 51.8% (week 6) and 64.8% (week 12) compared with polyglycolic acid controls (P < 0.01), as verified by X-ray, CT, and histology. Simvastatin increased migration capacity of BMSCs and EPCs in vitro (P < 0.05). Local simvastatin implant increased mobilization of EPCs to the peripheral blood by 127% revealed by FACS analysis (P < 0.01), and increased osteogenic BMSCs to the peripheral blood dramatically revealed by Alizarin Red-S staining for mineralized nodules formation. Pre-transplanted GFP-transfected BMSCs as a tracing cell and bioluminescence imaging revealed that local simvastatin implant recruited GFP-labeled BMSC. Also, local simvastatin implant induced the HIF-1α and BMP-2 expression. In conclusion, local simvastatin implantation promotes bone defect healing, where the underlying mechanism appears to involve the higher expression of HIF-1α and BMP-2, thus recruit autogenous osteogenic and angiogenetic stem cells to the bone defect area implanted with simvastatin.
authors.affiliation: Department of Orthopedics, Peking University Third Hospital, Beijing 100191, PR China.
authors.forename: Cui
authors.initials: C
authors.lastname: Yueyi
authors.forename: Han
authors.initials: H
authors.lastname: Xiaoguang
authors.forename: Wang
authors.initials: W
authors.lastname: Jingying
authors.forename: Song
authors.initials: S
authors.lastname: Quansheng
authors.forename: Tan
authors.initials: T
authors.lastname: Jie
authors.forename: Fu
authors.initials: F
authors.lastname: Xin
authors.forename: Xu
authors.initials: X
authors.lastname: Yingsheng
authors.forename: Song
authors.initials: S
authors.lastname: Chunli
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004343:Drug Implants / Q000494:pharmacology / Q000627:therapeutic use*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D012886:Skull / Q000187:drug effects* / Q000293:injuries*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D004343:Drug Implants; D000960:Hypolipidemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019821:Simvastatin
keywords: BMP-2; Bone healing; Endothelial progenitor cells; HIF-1α; Mesenchymal stem cell; Simvastatin