Angiogenesis in bone regeneration.

Angiogenesis is a key component of bone repair. New blood vessels bring oxygen and nutrients to the highly metabolically active regenerating callus and serve as a route for inflammatory cells and cartilage and bone precursor cells to reach the injury site. Angiogenesis is regulated by a variety of growth factors, notably vascular endothelial growth factor (VEGF), which are produced by inflammatory cells and stromal cells to induce blood vessel in-growth. A variety of studies with transgenic and gene-targeted mice have demonstrated the importance of angiogenesis in fracture healing, and have provided insights into regulatory processes governing fracture angiogenesis. Indeed, in animal models enhancing angiogenesis promotes bone regeneration, suggesting that modifying fracture vascularization could be a viable therapeutic approach for accelerated/improved bone regeneration clinically.

[1]  Hiromu Ito,et al.  Transforming growth factor-β1 mediates the effects of low-intensity pulsed ultrasound in chondrocytes , 2005 .

[2]  S. Lynch,et al.  Recombinant human platelet-derived growth factor: biology and clinical applications. , 2008, The Journal of bone and joint surgery. American volume.

[3]  Ana D. Lopez,et al.  An in vivo model for study of the angiogenic effects of basic fibroblast growth factor. , 1987, Biochemical and biophysical research communications.

[4]  M. Longaker,et al.  VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism. , 2000, American journal of physiology. Cell physiology.

[5]  Kozo Nakamura,et al.  Impaired bone fracture healing in matrix metalloproteinase-13 deficient mice. , 2007, Biochemical and biophysical research communications.

[6]  D. Gospodarowicz,et al.  Regulation of bovine bone cell proliferation by fibroblast growth factor and transforming growth factor beta. , 1988, Endocrinology.

[7]  M. Goldberg,et al.  Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. , 1988, Science.

[8]  Sheldon S. Lin,et al.  Low‐intensity pulsed ultrasound increases the fracture callus strength in diabetic BB Wistar rats but does not affect cellular proliferation , 2002, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[9]  D. Graves,et al.  Impaired Fracture Healing in the Absence of TNF‐α Signaling: The Role of TNF‐α in Endochondral Cartilage Resorption , 2003 .

[10]  Eric Hume,et al.  Power Doppler Assessment of Vascular Changes During Fracture Treatment With Low‐Intensity Ultrasound , 2003, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[11]  M. Bhandari,et al.  The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. , 2002, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[12]  Megas Panagiotis Classification of non-union. , 2005 .

[13]  I. Hvid,et al.  Recombinant human vascular endothelial growth factor enhances bone healing in an experimental nonunion model. , 2005, The Journal of bone and joint surgery. British volume.

[14]  M. Hadjiargyrou,et al.  Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair. , 2004, Bone.

[15]  J. Carballedo,et al.  Type III-B open tibial fractures in Mozambique , 1996, International Orthopaedics.

[16]  Diane Hu,et al.  Ischemia leads to delayed union during fracture healing: A mouse model , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[17]  Timo Jämsä,et al.  Adenoviral VEGF‐A gene transfer induces angiogenesis and promotes bone formation in healing osseous tissues , 2003, The journal of gene medicine.

[18]  Dong Yeon Lee,et al.  Mobilization of endothelial progenitor cells in fracture healing and distraction osteogenesis. , 2008, Bone.

[19]  D. Moore,et al.  Physiologic weight‐bearing increases new vessel formation during distraction osteogenesis: A micro‐tomographic imaging study , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[20]  S. Gold,et al.  Preliminary Results of Tibial Bone Transports With Pulsed Low Intensity Ultrasound (Exogen™) , 2005, Journal of Orthopaedics and Trauma.

[21]  S. Doty,et al.  Thrombin peptide (TP508) promotes fracture repair by up‐regulating inflammatory mediators, early growth factors, and increasing angiogenesis , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[22]  D. Hu,et al.  Effect of age on vascularization during fracture repair , 2008, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[23]  D. Graves,et al.  Tumor necrosis factor alpha (TNF-α) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing , 2005 .

[24]  G. Rodgers,et al.  Evidence of increased angiogenesis in patients with acute myeloid leukemia. , 2000, Blood.

[25]  D. Gebauer,et al.  Pulsed Low-Intensity Ultrasound: A New Salvage Procedure for Delayed Unions and Nonunions After Leg Lengthening in Children , 2005, Journal of pediatric orthopedics.

[26]  D. Stewart,et al.  Effect of cell‐based VEGF gene therapy on healing of a segmental bone defect , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[27]  C. Patterson,et al.  Enhanced expression of vascular endothelial growth factor in human SaOS-2 osteoblast-like cells and murine osteoblasts induced by insulin-like growth factor I. , 1996, Endocrinology.

[28]  J. Agudelo,et al.  Intramedullary nailing in open tibia fractures: a comparison of two techniques , 2004, International Orthopaedics.

[29]  D. Wink,et al.  CD47 Is Necessary for Inhibition of Nitric Oxide-stimulated Vascular Cell Responses by Thrombospondin-1* , 2006, Journal of Biological Chemistry.

[30]  Dieter Gebauer,et al.  Low-intensity pulsed ultrasound: effects on nonunions. , 2005, Ultrasound in medicine & biology.

[31]  D. E. Ashhurst,et al.  Exogenous fibroblast growth factors-1 and -2 do not accelerate fracture healing in the rabbit. , 1995, Acta orthopaedica Scandinavica.

[32]  K. Dickson,et al.  Delayed unions and nonunions of open tibial fractures. Correlation with arteriography results. , 1994, Clinical orthopaedics and related research.

[33]  Chao Wan,et al.  The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. , 2007, The Journal of clinical investigation.

[34]  M. Menger,et al.  Erythropoietin (EPO): EPO-receptor signaling improves early endochondral ossification and mechanical strength in fracture healing. , 2007, Life sciences.

[35]  P. Collin‐Osdoby,et al.  Basic Fibroblast Growth Factor Stimulates Osteoclast Recruitment, Development, and Bone Pit Resorption in Association With Angiogenesis In Vivo on the Chick Chorioallantoic Membrane and Activates Isolated Avian Osteoclast Resorption In Vitro , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  D. Stewart,et al.  Endothelial progenitor cells promote fracture healing in a segmental bone defect model , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[37]  Z. Werb,et al.  Role of Matrix Metalloproteinase 13 in Both Endochondral and Intramembranous Ossification during Skeletal Regeneration , 2007, PloS one.

[38]  G. Semenza,et al.  Enhanced Bone Regeneration Associated With Decreased Apoptosis in Mice With Partial HIF‐1α Deficiency , 2007 .

[39]  J. Capo,et al.  A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing , 2009, Acta orthopaedica.

[40]  D. Donner,et al.  Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. , 1995, International journal of hematology.

[41]  Kozo Nakamura,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Acceleration of Fracture Healing in Nonhuman Primates by Fibroblast Growth Factor-2 , 2022 .

[42]  Yu-Te Lin,et al.  Outcome Comparison between Free Muscle and Free Fasciocutaneous Flaps for Reconstruction of Distal Third and Ankle Traumatic Open Tibial Fractures , 2006, Plastic and reconstructive surgery.

[43]  Y. Kato,et al.  Local Application of Basic Fibroblast Growth Factor Minipellet Induces the Healing of Segmental Bony Defects in Rabbits , 1998, Calcified Tissue International.

[44]  S Meghji,et al.  In vitro effects of therapeutic ultrasound on cell proliferation, protein synthesis, and cytokine production by human fibroblasts, osteoblasts, and monocytes. , 1999, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[45]  A. Simpson,et al.  The vascularity of atrophic non-unions. , 2002, Injury.

[46]  J. Ryaby,et al.  Bone formation is enhanced by thrombin‐related peptide TP508 during distraction osteogenesis , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[47]  Kozo Nakamura,et al.  Single local injection of recombinant fibroblast growth factor‐2 stimulates healing of segmental bone defects in rabbits , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[48]  J L Peacock,et al.  Electrical treatment of tibial non-union: a prospective, randomised, double-blind trial. , 2003, Injury.

[49]  S. Ueng,et al.  Hyperbaric oxygen therapy mitigates the adverse effect of cigarette smoking on the bone healing of tibial lengthening: an experimental study on rabbits. , 1999, The Journal of trauma.

[50]  P. Bornstein,et al.  Thrombospondins as matricellular modulators of cell function. , 2001, The Journal of clinical investigation.

[51]  J. Kinney,et al.  Repair of rabbit segmental defects with the thrombin peptide, TP508 , 2004, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[52]  Gang Li,et al.  Nonsteroidal anti-inflammatory drug-induced fracture nonunion: an inhibition of angiogenesis? , 2006, The Journal of bone and joint surgery. American volume.

[53]  B. Swoboda,et al.  Expression of VEGF isoforms by epiphyseal chondrocytes during low-oxygen tension is HIF-1 alpha dependent. , 2004, Osteoarthritis and cartilage.

[54]  Cato T Laurencin,et al.  Fracture repair with ultrasound: clinical and cell-based evaluation. , 2008, The Journal of bone and joint surgery. American volume.

[55]  C. R. Howlett,et al.  Effect of platelet-derived growth factor on tibial osteotomies in rabbits. , 1994, Bone.

[56]  Hiroshi Fukuda,et al.  Recombinant Human Basic Fibroblast Growth Factor Accelerates Fracture Healing by Enhancing Callus Remodeling in Experimental Dog Tibial Fracture , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[57]  Chao Wan,et al.  Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[58]  W Lehmann,et al.  The role of angiogenesis in a murine tibial model of distraction osteogenesis. , 2004, Bone.

[59]  H. Redmond,et al.  Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Napoleone Ferrara,et al.  VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation , 1999, Nature Medicine.

[61]  I. Hvid,et al.  Effects of locally applied vascular endothelial growth factor (VEGF) and VEGF‐inhibitor to the rabbit tibia during distraction osteogenesis , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[62]  S. Lynch,et al.  Accelerated fracture healing in the geriatric, osteoporotic rat with recombinant human platelet‐derived growth factor‐bb and an injectable beta‐tricalcium phosphate/collagen matrix , 2008, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[63]  A. Ladd,et al.  Thrombin peptide TP508 stimulates cellular events leading to angiogenesis, revascularization, and repair of dermal and musculoskeletal tissues. , 2006, The Journal of bone and joint surgery. American volume.

[64]  M. Kacena,et al.  Development of a femoral non-union model in the mouse. , 2008, Injury.

[65]  A. Caplan,et al.  Mesenchymal stem cells as trophic mediators , 2006, Journal of cellular biochemistry.

[66]  J. Poser,et al.  Novel formulation of fibroblast growth factor‐2 in a hyaluronan gel accelerates fracture healing in nonhuman primates , 1999, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[67]  James B Hoying,et al.  The non‐proteolytically active thrombin peptide TP508 stimulates angiogenic sprouting , 2006, Journal of cellular physiology.

[68]  T. Einhorn,et al.  Spatial and temporal gene expression in chondrogenesis during fracture healing and the effects of basic fibroblast growth factor , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[69]  R. Spencer,et al.  The influence of pulsed low-intensity ultrasound on matrix production of chondrocytes at different stages of differentiation: an explant study. , 2002, Ultrasound in medicine & biology.

[70]  N. Ferrara Molecular and biological properties of vascular endothelial growth factor , 1999, Journal of Molecular Medicine.

[71]  A. Giaccia,et al.  Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development , 2004, Development.

[72]  Jill A. Helms,et al.  Altered fracture repair in the absence of MMP9 , 2003, Development.

[73]  X. Qin,et al.  Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. , 2005, The Annals of thoracic surgery.

[74]  A. Anagnostou,et al.  Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[75]  J F Greenleaf,et al.  Low‐intensity ultrasound stimulates proteoglycan synthesis in rat chondrocytes by increasing aggrecan gene expression , 1999, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[76]  E. Schwarz,et al.  Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. , 2002, The Journal of clinical investigation.

[77]  P. Giannoudis,et al.  The Synergistic Effect of Autograft and BMP-7 in the Treatment of Atrophic Nonunions , 2009, Clinical orthopaedics and related research.

[78]  A. M. Simon,et al.  Cyclo‐Oxygenase 2 Function Is Essential for Bone Fracture Healing , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[79]  G. Gurtner,et al.  Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. , 2005, Blood.

[80]  R. Guldberg,et al.  COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. , 2008, Bone.

[81]  A. Patwardhan,et al.  Tibial segmental defect repair: Chondrogenesis and biomechanical strength modulated by basic fibroblast growth factor , 1997, The Anatomical record.

[82]  Chao Wan,et al.  Bone Formation During Distraction Osteogenesis Is Dependent on Both VEGFR1 and VEGFR2 Signaling , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[83]  S. Goldstein,et al.  Thrombospondin-2 Influences the Proportion of Cartilage and Bone During Fracture Healing , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[84]  J. Isner,et al.  VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells , 1999, The EMBO journal.

[85]  Yukihide Iwamoto,et al.  Effects of FGF-2 on metaphyseal fracture repair in rabbit tibiae , 2003, Journal of Bone and Mineral Metabolism.

[86]  L. Orci,et al.  Basic fibroblast growth factor induces angiogenesis in vitro. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[87]  D Kaspar,et al.  Effects of Mechanical Factors on the Fracture Healing Process , 1998, Clinical orthopaedics and related research.

[88]  W. Cheung,et al.  Low Intensity Pulsed Ultrasound Stimulates Osteogenic Activity of Human Periosteal Cells , 2004, Clinical orthopaedics and related research.

[89]  R F Kilcoyne,et al.  Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound. , 1994, The Journal of bone and joint surgery. American volume.

[90]  Y. Harada,et al.  Low‐Intensity Pulsed Ultrasound Accelerates Rat Femoral Fracture Healing by Acting on the Various Cellular Reactions in the Fracture Callus , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[91]  W. R. Taylor,et al.  Impaired Angiogenesis, Early Callus Formation, and Late Stage Remodeling in Fracture Healing of Osteopontin‐Deficient Mice , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[92]  E. Ogata,et al.  Stimulation of fracture repair by recombinant human basic fibroblast growth factor in normal and streptozotocin-diabetic rats. , 1994, Endocrinology.

[93]  E. Mackenzie,et al.  Impact of Smoking on Fracture Healing and Risk of Complications in Limb-Threatening Open Tibia Fractures , 2005, Journal of orthopaedic trauma.