Expression of angiogenic factors during distraction osteogenesis.
Distraction osteogenesis is a unique and effective way to treat limb length inequality resulting from congenital and posttraumatic skeletal defects. However, despite its widespread clinical use, the cellular and molecular mechanisms by which this surgical treatment promotes new bone formation are not well understood. Previous studies in distraction osteogenesis have noted increased blood flow and vessel formation within the zone of distraction. These observations suggest that distraction osteogenesis may be driven in part by an angiogenic process. Using immunohistological analysis, the expression of two different angiogenic factors (VEGF and bFGF) was shown to localize at the leading edge of the distraction gap, where nascent osteogenesis was occurring. These cells were spatially adjacent to new vessels that were identified by staining for factor VIII. Microarray analysis detected maximal mRNA expression for a wide variety of angiogenic factors including angiopoietin 1 and 2, both Tie receptors, VEGF-A and -D, VEGFR2, and neuropilin 1. Expression of these factors was found to be maximal during the phase of active distraction. Expression of mRNA for extracellular matrix proteins and BMPs was also maximal during this period. A comparison between the patterns of gene expression in fracture healing and distraction osteogenesis revealed similarities; however, the expression of a number of genes showed selective expression in these two types of bone healing. These data suggest that bone formation during distraction osteogenesis is accompanied by the robust induction of factors associated with angiogenesis and support further investigations to elucidate the mechanisms by which angiogenic events promote bone repair and regeneration.
Pacicca
D M
DM
Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Boston University Medical Center, 715 Albany Street, R-205, Boston, MA 02118-2526, USA. dmpacicca@cmh.edu
Patel
N
N
Lee
C
C
Salisbury
K
K
Lehmann
W
W
Carvalho
R
R
Gerstenfeld
L C
LC
Einhorn
T A
TA
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D042682:Angiopoietins / Q000235:genetics; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D003094:Collagen / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005269:Femur / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016222:Fibroblast Growth Factor 2 / Q000032:analysis / Q000235:genetics; D017102:Fracture Healing / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D020869:Gene Expression Profiling; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008297:Male; D018919:Neovascularization, Physiologic / Q000235:genetics; D039921:Neuropilins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D019857:Osteogenesis, Distraction; D053495:Osteopontin; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D042764:Receptors, TIE / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053781:Transforming Growth Factor beta2; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000235:genetics; D014841:von Willebrand Factor / Q000032:analysis
D043925:Angiogenesis Inducing Agents; D042682:Angiopoietins; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039921:Neuropilins; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D016222:Fibroblast Growth Factor 2; D015675:Osteocalcin; D053495:Osteopontin; C066845:pleiotrophin; D003094:Collagen; C496373:Fgfr4 protein, rat; D051499:Receptor, Fibroblast Growth Factor, Type 4; D042764:Receptors, TIE; D040262:Receptors, Vascular Endothelial Growth Factor