Bringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration.

Bone has the unique capacity to heal without the formation of a fibrous scar, likely because several of the cellular and molecular processes governing bone healing recapitulate the events during skeletal development. A critical component in bone healing is the timely appearance of blood vessels in the fracture callus. Angiogenesis, the formation of new blood vessels from pre-existing ones, is stimulated after fracture by the local production of numerous angiogenic growth factors. The fracture vasculature not only supplies oxygen and nutrients, but also stem cells able to differentiate into osteoblasts and in a later phase also the ions necessary for mineralization. This review provides a concise report of the regulation of angiogenesis by bone cells, its importance during bone healing and its possible therapeutic applications in bone tissue engineering. This article is part of a Special Issue entitled "Stem Cells and Bone".

[1]  D. Mooney,et al.  Combined Angiogenic and Osteogenic Factor Delivery Enhances Bone Marrow Stromal Cell‐Driven Bone Regeneration , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

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

[3]  C. Deng,et al.  TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation , 2012, International journal of biological sciences.

[4]  H. Moses,et al.  Transforming growth factor beta 1-induced changes in cell migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane , 1990, The Journal of cell biology.

[5]  P. Carmeliet,et al.  Increased skeletal VEGF enhances β‐catenin activity and results in excessively ossified bones , 2010, The EMBO journal.

[6]  G. Paiement,et al.  The importance of the blood supply in the healing of tibial fractures. , 1995, Contemporary orthopaedics.

[7]  C. Kirkpatrick,et al.  Retention of a differentiated endothelial phenotype by outgrowth endothelial cells isolated from human peripheral blood and expanded in long-term cultures , 2006, Cell and Tissue Research.

[8]  Rui L Reis,et al.  Crosstalk between osteoblasts and endothelial cells co-cultured on a polycaprolactone-starch scaffold and the in vitro development of vascularization. , 2009, Biomaterials.

[9]  J. Partanen,et al.  Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. , 2006, Developmental biology.

[10]  S. Dong,et al.  MicroRNAs regulate osteogenesis and chondrogenesis. , 2012, Biochemical and biophysical research communications.

[11]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[12]  S. Venkatraman,et al.  Effect of pore size and interpore distance on endothelial cell growth on polymers. , 2008, Journal of biomedical materials research. Part A.

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

[14]  S. Antonini,et al.  Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. , 2011, Nature communications.

[15]  R. Gutiérrez,et al.  Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. , 1992, Clinical orthopaedics and related research.

[16]  R. Guldberg,et al.  Periosteal Progenitor Cell Fate in Segmental Cortical Bone Graft Transplantations: Implications for Functional Tissue Engineering , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  M. Klagsbrun,et al.  Neuropilin‐1 expression in osteogenic cells: Down‐regulation during differentiation of osteoblasts into osteocytes , 2001, Journal of cellular biochemistry.

[18]  S. Papapoulos,et al.  Bone Morphogenetic Proteins Stimulate Angiogenesis through Osteoblast-Derived Vascular Endothelial Growth Factor A. , 2002, Endocrinology.

[19]  T. Clemens,et al.  Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration , 2008, Proceedings of the National Academy of Sciences.

[20]  D. Kaplan,et al.  Porosity of 3D biomaterial scaffolds and osteogenesis. , 2005, Biomaterials.

[21]  Stephen M Warren,et al.  Factors in the fracture microenvironment induce primary osteoblast angiogenic cytokine production. , 2002, Plastic and reconstructive surgery.

[22]  C. Garlanda,et al.  Heterogeneity of endothelial cells. Specific markers. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[23]  C James Kirkpatrick,et al.  The rapid anastomosis between prevascularized networks on silk fibroin scaffolds generated in vitro with cocultures of human microvascular endothelial and osteoblast cells and the host vasculature. , 2010, Biomaterials.

[24]  M. Ito,et al.  Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. , 2000, The Journal of clinical investigation.

[25]  M. Schaffler,et al.  Prevention of fracture healing in rats by an inhibitor of angiogenesis. , 2001, Bone.

[26]  Tzu-Wei Wang,et al.  Coculture of endothelial and smooth muscle cells on a collagen membrane in the development of a small-diameter vascular graft. , 2007, Biomaterials.

[27]  A. Rabie,et al.  Recombinant AAV-mediated VEGF gene therapy induces mandibular condylar growth , 2007, Gene Therapy.

[28]  Jan Schrooten,et al.  Engineering Vascularized Bone: Osteogenic and Proangiogenic Potential of Murine Periosteal Cells , 2012, Stem cells.

[29]  Xiaogang Wang,et al.  miR-214 targets ATF4 to inhibit bone formation , 2012, Nature Medicine.

[30]  Linda G Griffith,et al.  Engineering principles of clinical cell-based tissue engineering. , 2004, The Journal of bone and joint surgery. American volume.

[31]  C. Patterson,et al.  Selective endothelial cell attachment to peptide-modified terpolymers. , 2008, Biomaterials.

[32]  William Bonfield,et al.  Designing porous scaffolds for tissue engineering , 2006, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[33]  Hyun-Jai Cho,et al.  Cytokines and Matrix Metalloproteinases Progenitor Cells and Late Outgrowth Endothelial Cells: the Role of Angiogenic Synergistic Neovascularization by Mixed Transplantation of Early Endothelial Synergistic Neovascularization by Mixed Transplantation of Early Endothelial Progenitor Cells and Late Ou , 2022 .

[34]  David J Mooney,et al.  VEGF Scaffolds Enhance Angiogenesis and Bone Regeneration in Irradiated Osseous Defects , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  T. Einhorn Mechanisms of fracture healing. , 1991, Hospital practice.

[36]  Jean Vacher,et al.  A microRNA expression signature of osteoclastogenesis. , 2011, Blood.

[37]  A. Bikfalvi,et al.  The role of fibroblast growth factors in vascular development. , 2002, Trends in molecular medicine.

[38]  Eleftherios Tsiridis,et al.  Current concepts of molecular aspects of bone healing. , 2005, Injury.

[39]  Ben D. MacArthur,et al.  Mesenchymal and haematopoietic stem cells form a unique bone marrow niche , 2010, Nature.

[40]  W. Puhl,et al.  Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. , 2002, Bone.

[41]  N. Itoh,et al.  FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. , 2002, Genes & development.

[42]  S. Matsuda,et al.  Inhibition of miR‐92a Enhances Fracture Healing via Promoting Angiogenesis in a Model of Stabilized Fracture in Young Mice , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[43]  Kozo Nakamura,et al.  Regulation of Osteoblast, Chondrocyte, and Osteoclast Functions by Fibroblast Growth Factor (FGF)-18 in Comparison with FGF-2 and FGF-10* , 2002, The Journal of Biological Chemistry.

[44]  Mike Barbeck,et al.  Rapid vascularization of starch–poly(caprolactone) in vivo by outgrowth endothelial cells in co‐culture with primary osteoblasts , 2011, Journal of tissue engineering and regenerative medicine.

[45]  A. Bergman,et al.  Arteriolar niches maintain haematopoietic stem cell quiescence , 2013, Nature.

[46]  Lei Yuan,et al.  Engineering Robust and Functional Vascular Networks In Vivo With Human Adult and Cord Blood–Derived Progenitor Cells , 2008, Circulation research.

[47]  H. V. von Recum,et al.  Endothelial stem cells and precursors for tissue engineering: cell source, differentiation, selection, and application. , 2008, Tissue engineering. Part B, Reviews.

[48]  David J. Mooney,et al.  Spatio–temporal VEGF and PDGF Delivery Patterns Blood Vessel Formation and Maturation , 2007, Pharmaceutical Research.

[49]  Guoping Chen,et al.  Cellular control of tissue architectures using a three-dimensional tissue fabrication technique. , 2007, Biomaterials.

[50]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[51]  L. Orci,et al.  Alpha-smooth muscle actin, a differentiation marker of smooth muscle cells, is present in microfilamentous bundles of pericytes. , 1989, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[52]  J. Veerkamp,et al.  Loading of collagen-heparan sulfate matrices with bFGF promotes angiogenesis and tissue generation in rats. , 2002, Journal of biomedical materials research.

[53]  Xu Cao,et al.  BMP signaling in skeletal development. , 2005, Biochemical and biophysical research communications.

[54]  F. Mallein-Gerin,et al.  VEGF and VEGF receptors are differentially expressed in chondrocytes. , 2007, Bone.

[55]  Charles P. Lin,et al.  Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. , 2012, Cell stem cell.

[56]  C. Brighton,et al.  Oxygen tension of healing fractures in the rabbit. , 1972, The Journal of bone and joint surgery. American volume.

[57]  Anthony Atala,et al.  Principals of neovascularization for tissue engineering. , 2002, Molecular aspects of medicine.

[58]  Ulrich Wagner,et al.  Follicular Dendritic Cells Emerge from Ubiquitous Perivascular Precursors , 2012, Cell.

[59]  D. Ornitz,et al.  FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. , 2007, Developmental biology.

[60]  B. Zheng,et al.  The dose of growth factors influences the synergistic effect of vascular endothelial growth factor on bone morphogenetic protein 4-induced ectopic bone formation. , 2009, Tissue engineering. Part A.

[61]  B. Olsen,et al.  Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. , 2002, Development.

[62]  A. Luttun,et al.  Vascular progenitors: from biology to treatment. , 2002, Trends in cardiovascular medicine.

[63]  Holger Gerhardt,et al.  Basic and Therapeutic Aspects of Angiogenesis , 2011, Cell.

[64]  M. Hristov,et al.  Endothelial progenitor cells: isolation and characterization. , 2003, Trends in cardiovascular medicine.

[65]  S. Elledge,et al.  Dicer is essential for mouse development , 2003, Nature Genetics.

[66]  K. Alitalo,et al.  Molecular regulation of angiogenesis and lymphangiogenesis , 2007, Nature Reviews Molecular Cell Biology.

[67]  Gabriele Bergers,et al.  MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes , 1998, Cell.

[68]  Johnny Huard,et al.  Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. , 2002, The Journal of clinical investigation.

[69]  V. Midy,et al.  Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. , 1994, Biochemical and biophysical research communications.

[70]  Matthias P Lutolf,et al.  Biopolymeric delivery matrices for angiogenic growth factors. , 2003, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[71]  Douglas J Adams,et al.  In Vivo Fate Mapping Identifies Mesenchymal Progenitor Cells , 2011, Stem cells.

[72]  R. W. Rauser,et al.  Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[73]  W. Stallcup,et al.  NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[74]  Johan Lammens,et al.  The Pentaconcept in skeletal tissue engineering. A combined approach for the repair of bone defects. , 2012, Acta orthopaedica Belgica.

[75]  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.

[76]  P. Giannoudis,et al.  The diamond concept--open questions. , 2008, Injury.

[77]  C. Colnot Cellular and molecular interactions regulating skeletogenesis , 2005, Journal of cellular biochemistry.

[78]  C A van Blitterswijk,et al.  3D fiber-deposited scaffolds for tissue engineering: influence of pores geometry and architecture on dynamic mechanical properties. , 2006, Biomaterials.

[79]  H. Gerhardt,et al.  Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting , 2010, Nature Cell Biology.

[80]  B. Sumpio,et al.  Cells in focus: endothelial cell. , 2002, The international journal of biochemistry & cell biology.

[81]  A. Caplan,et al.  PDGF in bone formation and regeneration: New insights into a novel mechanism involving MSCs , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[82]  P. Marie Fibroblast growth factor signaling controlling bone formation: an update. , 2012, Gene.

[83]  M. Adachi,et al.  Expression of angiopoietin-1 in osteoblasts and its inhibition by tumor necrosis factor-alpha and interferon-gamma. , 2007, Translational research : the journal of laboratory and clinical medicine.

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

[85]  Theodore Miclau,et al.  Does adult fracture repair recapitulate embryonic skeletal formation? , 1999, Mechanisms of Development.

[86]  Y. Gho,et al.  DJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling , 2012, Nature Communications.

[87]  H. Hansson,et al.  Transient expression of insulin-like growth factor I immunoreactivity by vascular cells during angiogenesis. , 1989, Experimental and molecular pathology.

[88]  Y. Toyama,et al.  Osteoblast-specific Angiopoietin 1 overexpression increases bone mass. , 2007, Biochemical and biophysical research communications.

[89]  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.

[90]  R. Lovell-Badge,et al.  The Vascular Stem Cell Niche , 2012, Journal of Cardiovascular Translational Research.

[91]  M. Longaker,et al.  Transforming growth factor- b 1 modulates the expression of vascular endothelial growth factor by osteoblasts , 1999 .

[92]  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.

[93]  S. Badylak,et al.  A perivascular origin for mesenchymal stem cells in multiple human organs. , 2008, Cell stem cell.

[94]  M. Longaker,et al.  Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. , 2002, Plastic and reconstructive surgery.

[95]  A. Nguyen,et al.  Natural history of mesenchymal stem cells, from vessel walls to culture vessels , 2013, Cellular and Molecular Life Sciences.

[96]  D. Ornitz,et al.  Fibroblast growth factor expression during skeletal fracture healing in mice , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[97]  Geert Carmeliet,et al.  Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair. , 2006, The Journal of clinical investigation.

[98]  Rozalia Dimitriou,et al.  Bone regeneration: current concepts and future directions , 2011, BMC medicine.

[99]  B. Sacchetti,et al.  Self-Renewing Osteoprogenitors in Bone Marrow Sinusoids Can Organize a Hematopoietic Microenvironment , 2007, Cell.

[100]  Kozo Nakamura,et al.  Regulation of Osteoclast Differentiation by Fibroblast Growth Factor 2: Stimulation of Receptor Activator of Nuclear Factor κB Ligand/Osteoclast Differentiation Factor Expression in Osteoblasts and Inhibition of Macrophage Colony‐Stimulating Factor Function in Osteoclast Precursors , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[101]  P. Carmeliet,et al.  PlGF: a multitasking cytokine with disease-restricted activity. , 2012, Cold Spring Harbor perspectives in medicine.

[102]  Rakesh K Jain,et al.  Molecular regulation of vessel maturation , 2003, Nature Medicine.

[103]  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.

[104]  J. Gimble,et al.  Multipotential human adipose‐derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo , 2008, Journal of cellular physiology.

[105]  Bo Liu,et al.  MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. , 2009, Lung cancer.

[106]  R. Baron,et al.  Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. , 2012, The Journal of clinical investigation.

[107]  David Botstein,et al.  Endothelial cell diversity revealed by global expression profiling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[108]  E. Brogi,et al.  Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. , 1994, The Journal of clinical investigation.

[109]  J. Jośko,et al.  Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. , 2000, Medical science monitor : international medical journal of experimental and clinical research.

[110]  Marcel Karperien,et al.  Printed in U.S.A. Copyright © 2000 by The Endocrine Society Expression of Vascular Endothelial Growth Factors and Their Receptors during Osteoblast Differentiation , 2022 .

[111]  Subrata Chakrabarti,et al.  MicroRNA-200b Regulates Vascular Endothelial Growth Factor–Mediated Alterations in Diabetic Retinopathy , 2011, Diabetes.

[112]  G. Semenza,et al.  Hypoxia-Inducible Factors in Physiology and Medicine , 2012, Cell.

[113]  Rui L Reis,et al.  Vascularization in bone tissue engineering: physiology, current strategies, major hurdles and future challenges. , 2010, Macromolecular bioscience.

[114]  J. Ward,et al.  MT1-MMP-Deficient Mice Develop Dwarfism, Osteopenia, Arthritis, and Connective Tissue Disease due to Inadequate Collagen Turnover , 1999, Cell.

[115]  M. Longaker,et al.  Fgf-9 is required for angiogenesis and osteogenesis in long bone repair , 2010, Proceedings of the National Academy of Sciences.

[116]  D J Mooney,et al.  Bone Regeneration via a Mineral Substrate and Induced Angiogenesis , 2004, Journal of dental research.

[117]  S. Scaglione,et al.  Short-time survival and engraftment of bone marrow stromal cells in an ectopic model of bone regeneration. , 2010, Tissue engineering. Part A.

[118]  M. Longaker,et al.  Mechanisms of fibroblast growth factor-2 modulation of vascular endothelial growth factor expression by osteoblastic cells. , 2000, Endocrinology.

[119]  J. Glowacki Angiogenesis in fracture repair. , 1998, Clinical orthopaedics and related research.

[120]  F. Minuto,et al.  The IGF system and bone. , 2005, Journal of endocrinological investigation.

[121]  Geert Carmeliet,et al.  Hypoxia-driven pathways in bone development, regeneration and disease , 2012, Nature Reviews Rheumatology.

[122]  P. Negri-Cesi,et al.  In Vitro Effects of PDGF Isoforms (AA, BB, AB and CC) on Migration and Proliferation of SaOS-2 Osteoblasts and on Migration of Human Osteoblasts , 2009, International journal of biomedical science : IJBS.