title: Effect of age on vascularization during fracture repair.
abstract: Age affects fracture repair; however, the underlying mechanisms are not well understood. The goal of this study was to assess the effects that age has on vascularization during fracture healing. Tibial fractures were created in juvenile (4-week-old), middle-aged (6-month-old), and elderly (18-month-old) mice. The length density and surface density of blood vessels within fracture calluses were analyzed using stereology at 7 days after fracture. The expression of molecules that regulate vascular invasion of the fracture callus was also compared among the three age groups by immunohistochemistry and in situ hybridization. At 7 days after fracture, juvenile mice had a higher surface density of blood vessels compared to the middle-aged and elderly. Hypoxia-inducible factor-1 alpha protein and transcripts of vascular endothelial growth factor were detected at 3 days postinjury in juvenile but not middle-aged and elderly mice. Stronger Mmp-9 and -13 expression was detected in fracture calluses at day 7 in the juvenile compared to the middle-aged and elderly mice. At 21 days postfracture, expression of both Mmps was more robust in the elderly than juvenile and middle-aged animals. These data indicate that age affects vascularization during fracture repair, and the changes we observed are directly correlated with altered expression of biochemical factors that regulate the process of angiogenesis. However, whether the increased vascularization is the cause or result of accelerated bone repair in juvenile animals remains unknown. Nonetheless, our results indicate that enhancing vascularization during fracture repair in the elderly may provide unique therapeutic opportunities.
authors.affiliation: Department of Orthopaedic Surgery, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Lu
authors.forename: Erik
authors.initials: E
authors.lastname: Hansen
authors.forename: Anna
authors.initials: A
authors.lastname: Sapozhnikova
authors.forename: Diane
authors.initials: D
authors.lastname: Hu
authors.forename: Theodore
authors.initials: T
authors.lastname: Miclau
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Marcucio
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D002146:Bony Callus / Q000033:anatomy & histology / Q000098:blood supply* / Q000378:metabolism; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000502:physiology*; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013978:Tibial Fractures / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9