Angiogenesis and bone repair.

The intimate connection, both physical and biochemical, between blood vessels and bone cells has long been recognized. Genetic, biochemical, and pharmacological studies have identified and characterized factors involved in the conversation between endothelial cells (EC) and osteoblasts (OB) during both bone formation and repair. The long-awaited FDA approval of two growth factors, BMP-2 and OP-1, with angiogenic and osteogenic activity confirms the importance of these two processes in human skeletal healing. In this review, the role of osteogenic factors in the adaptive response and interactive function of OB and EC during the multi-step process of bone repair will be discussed.

[1]  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 .

[2]  Toshitaka Nakamura,et al.  Vascular endothelial growth factor is expressed along with its receptors during the healing process of bone and bone marrow after drill-hole injury in rats. , 2003, Bone.

[3]  E. Wagner,et al.  Conditional inactivation of VEGF-A in areas of collagen2a1 expression results in embryonic lethality in the heterozygous state. , 2000, Development.

[4]  Linshu Liu,et al.  Inductive activity of recombinant human growth and differentiation factor-5. , 2000, Biochemical Society transactions.

[5]  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.

[6]  M. Noda,et al.  In vivo stimulation of bone formation by transforming growth factor-beta. , 1989, Endocrinology.

[7]  M. Bostrom,et al.  Transforming growth factor beta in fracture repair. , 1998, Clinical orthopaedics and related research.

[8]  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.

[9]  R. Cancedda,et al.  Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation. J Cell Sci 113(Pt 1):59-69 , 2000 .

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

[11]  H. Oppermann,et al.  Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. , 1992, The Journal of biological chemistry.

[12]  E. Amento,et al.  Rapid publication TGF‐β1 induces bone closure of skull defects , 1991 .

[13]  S. Duursma,et al.  Growth hormone is mitogenic for fetal mouse osteoblasts but not for undifferentiated bone cells. , 1988, The Journal of endocrinology.

[14]  V. Rosen,et al.  The healing of segmental bone defects, induced by recombinant human bone morphogenetic protein (rhBMP-2). A radiographic, histological, and biomechanical study in rats. , 1992, The Journal of bone and joint surgery. American volume.

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

[16]  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.

[17]  J. Poser,et al.  Spinal fusion with recombinant human growth and differentiation factor‐5 combined with a mineralized collagen matrix , 2001, The Anatomical record.

[18]  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.

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

[20]  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.

[21]  K. Tanne,et al.  Expression of Vascular Endothelial Growth Factor and the Effects on Bone Remodeling during Experimental Tooth Movement , 2003, Journal of dental research.

[22]  T. Fotsis,et al.  The N-myc oncogene in human neuroblastoma cells: down-regulation of an angiogenesis inhibitor identified as activin A. , 2000, Cancer research.

[23]  R. Cancedda,et al.  Parathyroid Hormone [PTH(1–34)] and Parathyroid Hormone–Related Protein [PTHrP(1–34)] Promote Reversion of Hypertrophic Chondrocytes to a Prehypertrophic Proliferating Phenotype and Prevent Terminal Differentiation of Osteoblast‐like Cells , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[24]  S. Fujita,et al.  Activin increases bone mass and mechanical strength of lumbar vertebrae in aged ovariectomized rats. , 2000, Bone.

[25]  V. Mandracchia,et al.  Current concepts of bone healing. , 2001, Clinics in podiatric medicine and surgery.

[26]  V. Rosen,et al.  Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. , 1998, Clinical orthopaedics and related research.

[27]  A. Reddi Bone Morphogenetic Proteins: From Basic Science to Clinical Applications , 2001, The Journal of bone and joint surgery. American volume.

[28]  F. W. Rhinelander,et al.  Tibial blood supply in relation to fracture healing. , 1974, Clinical orthopaedics and related research.

[29]  R. L. Hall,et al.  Preclinical Safety Evaluation of rhuMAbVEGF, an Antiangiogenic Humanized Monoclonal Antibody , 1999, Toxicologic pathology.

[30]  L. Raisz,et al.  Effects of acid and basic fibroblast growth factor and heparin on resorption of cultured fetal rat long bones , 1991, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[31]  J. Heckman,et al.  Bone morphogenetic protein but not transforming growth factor-beta enhances bone formation in canine diaphyseal nonunions implanted with a biodegradable composite polymer. , 1999, The Journal of bone and joint surgery. American volume.

[32]  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.

[33]  D. E. Ashhurst,et al.  The effect of exogenous transforming growth factor-beta 2 on healing fractures in the rabbit. , 1995, Bone.

[34]  J. Michael Kabo,et al.  Evaluation of rhBMP‐2 With an OPLA Carrier in a Canine Posterolateral (Transverse Process) Spinal Fusion Model , 1995, Spine.

[35]  S. Bulstra,et al.  Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect , 1999 .

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

[37]  S. Cook,et al.  In Vivo Evaluation of Recombinant Human Osteogenic Protein (rhOP-1) Implants As a Bone Graft Substitute for Spinal Fusions , 1994, Spine.

[38]  H. Redmond,et al.  Is human fracture hematoma inherently angiogenic , 2000 .

[39]  M. Bolander,et al.  Transforming growth factor-beta in the regulation of fracture repair. , 1990, The Orthopedic clinics of North America.

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

[41]  M E Bolander,et al.  Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur , 1990, The Journal of cell biology.

[42]  Hongshik Ahn,et al.  Transcriptional Profiling of Bone Regeneration , 2002, The Journal of Biological Chemistry.

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

[44]  J. Wozney,et al.  Bone Morphogenetic Protein-2 Increases the Rate of Callus Formation after Fracture of the Rabbit Tibia , 1999, Calcified Tissue International.

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

[46]  R. Balderston,et al.  Clinical and Radiographic Outcomes of Anterior Lumbar Interbody Fusion Using Recombinant Human Bone Morphogenetic Protein-2 , 2002, Spine.

[47]  H. Seeherman,et al.  Recombinant Human Bone Morphogenetic Protein‐2 Enhances Osteotomy Healing in Glucocorticoid‐Treated Rabbits , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[48]  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.

[49]  R J O'Keefe,et al.  The potential role of transforming growth factor beta in fracture healing. , 1998, Clinical orthopaedics and related research.

[50]  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 .

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

[52]  M. Kumegawa,et al.  Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts , 2000, FEBS letters.

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

[54]  M. Kellomäki,et al.  Inability of transforming growth factor-β1, combined with a bioabsorbable polymer paste, to promote healing of bone defects in the rat distal femur , 2001, Archives of Orthopaedic and Trauma Surgery.

[55]  U. Ripamonti,et al.  Osteogenic protein‐1, a bone morphogenetic protein, induces angiogenesis in the chick chorioallantoic membrane and synergizes with basic fibroblast growth factor and transforming growth factor‐β1 , 2000, The Anatomical record.

[56]  T. White,et al.  Pleistocene Homo sapiens from Middle Awash, Ethiopia , 2003, Nature.

[57]  M. Longaker,et al.  The BMP antagonist noggin regulates cranial suture fusion , 2003, Nature.

[58]  A. Reddi,et al.  Complete regeneration of bone in the baboon by recombinant human osteogenic protein-1 (hOP-1, bone morphogenetic protein-7). , 1996, Growth factors.

[59]  S. Vukicevic,et al.  An EP2 receptor-selective prostaglandin E2 agonist induces bone healing , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[60]  H. Oxlund,et al.  Local injection of TGF-β increases the strength of tibial fractures in the rat , 1994 .

[61]  J. Lemonnier,et al.  Bone Morphogenetic Protein-2 Promotes Osteoblast Apoptosis through a Smad-independent, Protein Kinase C-dependent Signaling Pathway* , 2001, The Journal of Biological Chemistry.

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

[63]  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.

[64]  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.

[65]  Kanji Sato,et al.  Anabolic effects of 1,25-dihydroxyvitamin D3 on osteoblasts are enhanced by vascular endothelial growth factor produced by osteoblasts and by growth factors produced by endothelial cells. , 1997, Endocrinology.

[66]  Kozo Nakamura,et al.  Direct and Indirect Actions of Fibroblast Growth Factor 2 on Osteoclastic Bone Resorption in Cultures , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[67]  J. Galante,et al.  Enhancement of bone ingrowth by transforming growth factor-beta. , 1995, The Journal of bone and joint surgery. American volume.

[68]  M. Fukuda,et al.  Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone. , 2000, European journal of histochemistry : EJH.

[69]  S. Cook,et al.  Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. , 1994, Clinical orthopaedics and related research.

[70]  S. Mochizuki,et al.  Basic fibroblast growth factor induces osteoclast formation by reciprocally regulating the production of osteoclast differentiation factor and osteoclastogenesis inhibitory factor in mouse osteoblastic cells. , 1999, Biochemical and biophysical research communications.

[71]  J. Hunter A treatise on the blood, inflammation, and gunshot wounds , 1817 .

[72]  G. Wesolowski,et al.  Effects of acidic and basic fibroblast growth factors on osteoblastic cells. , 1989, Connective tissue research.

[73]  C. Bünger,et al.  TRANSFORMING GROWTH FACTOR-β1 STIMULATES BONE ONGROWTH TO WEIGHT-LOADED TRICALCIUM PHOSPHATE COATED IMPLANTS: AN EXPERIMENTAL STUDY IN DOGS , 1996 .

[74]  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.

[75]  M. Matzuk,et al.  Genetic Analysis of the Mammalian Transforming Growth Factor-β Superfamily , 2002 .

[76]  R. Derynck,et al.  Osteoblastic Responses to TGF-β during Bone Remodeling , 1998 .

[77]  P. Maher,et al.  Distribution of Fibroblast Growth Factor (FGF)-2 and FGF Receptor-1 Messenger RNA Expression and Protein Presence in the Mid-Trimester Human Fetus , 1996, Pediatric Research.

[78]  M. Taylor,et al.  Maxillary sinus augmentation in the non-human primate: a comparative radiographic and histologic study between recombinant human osteogenic protein-1 and natural bone mineral. , 1998, Journal of periodontology.

[79]  M. Urist Bone: Formation by Autoinduction , 1965, Science.

[80]  G. Muschler,et al.  Evaluation of Human Bone Morphogenetic Protein 2 in a Canine Spinal Fusion Model , 1994, Clinical orthopaedics and related research.

[81]  K. Nakamura,et al.  Stimulation of bone formation by intraosseous injection of basic fibroblast growth factor in ovariectomised rats , 1998, International Orthopaedics.

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

[83]  Thomas A Einhorn,et al.  Differential Temporal Expression of Members of the Transforming Growth Factor β Superfamily During Murine Fracture Healing , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[84]  C. Brighton,et al.  Early histological and ultrastructural changes in medullary fracture callus. , 1991, The Journal of bone and joint surgery. American volume.

[85]  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.

[86]  M. Shibuya,et al.  Increase of vascular endothelial growth factor mRNA expression by 1,25‐dihydroxyvitamin D3 in human osteoblast‐like cells , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[87]  T A Einhorn,et al.  Growth Factor Regulation of Fracture Repair , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[88]  J. Wozney,et al.  Clinical evaluation of recombinant human bone morphogenetic protein-2. , 2002, Clinical orthopaedics and related research.

[89]  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.

[90]  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.

[91]  V. Rosen,et al.  Recombinant human bone morphogenetic protein induces bone formation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[92]  G. Ilizarov,et al.  Reconstruction of large defects of blood vessels on extremities by means of a gradual distraction. (An experimental study). , 1980, Acta chirurgiae plasticae.

[93]  M. Ward,et al.  Parathyroid-induced angiogenesis is VEGF-dependent. , 2000, Surgery.

[94]  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.

[95]  V. Rosen,et al.  Identification of transforming growth factor beta family members present in bone-inductive protein purified from bovine bone. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[96]  S. Nishikawa,et al.  Vascular Endothelial Growth Factor Can Substitute for Macrophage Colony-Stimulating Factor in the Support of Osteoclastic Bone Resorption , 1999, The Journal of experimental medicine.

[97]  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.

[98]  H. Seeherman,et al.  Recombinant Human Bone Morphogenetic Protein-2 Accelerates Healing in a Rabbit Ulnar Osteotomy Model , 2001, The Journal of bone and joint surgery. American volume.

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

[100]  D. E. Ashhurst,et al.  The effects of age on the response of rabbit periosteal osteoprogenitor cells to exogenous transforming growth factor-beta 2. , 1994, Journal of cell science.

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

[102]  M. Capdevielle,et al.  Angiogenic activity of anterior pituitary tissue and growth hormone on the chick embryo chorio-allantoic membrane: a novel action of GH. , 1995, Life sciences.

[103]  Kjeld Søballe,et al.  Transforming growth factor-β enhances fracture healing in rabbit tibiae , 1993 .

[104]  D. Marsh,et al.  Concepts of fracture union, delayed union, and nonunion. , 1998, Clinical orthopaedics and related research.

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

[106]  K. Mizuno,et al.  The osteogenetic potential of fracture haematoma. Subperiosteal and intramuscular transplantation of the haematoma. , 1990, The Journal of bone and joint surgery. British volume.

[107]  T A Einhorn,et al.  The cell and molecular biology of fracture healing. , 1998, Clinical orthopaedics and related research.

[108]  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.

[109]  S. T. Yoon,et al.  Osteoinductive Molecules in Orthopaedics: Basic Science and Preclinical Studies , 2002, Clinical orthopaedics and related research.

[110]  C. Heldin,et al.  Platelet-derived growth factor is angiogenic in vivo. , 1992, Growth factors.

[111]  G. Schmidmaier,et al.  Quantitative measurement of the splice variants 120 and 164 of the angiogenic peptide vascular endothelial growth factor in the time flow of fracture healing: a study in the rat , 2002, Cell and Tissue Research.

[112]  T. Nakamura,et al.  Stimulation of endosteal bone formation by systemic injections of recombinant basic fibroblast growth factor in rats. , 1995, Endocrinology.

[113]  V. Rosen,et al.  Novel regulators of bone formation: molecular clones and activities. , 1988 .

[114]  D. Hu,et al.  Molecular aspects of healing in stabilized and non‐stabilized fractures , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[115]  T A Einhorn,et al.  Enhancement of fracture-healing. , 1995, The Journal of bone and joint surgery. American volume.

[116]  O. Reikerås,et al.  The importance of the hematoma for fracture healing in rats. , 1993, Acta orthopaedica Scandinavica.

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

[118]  V. Kosma,et al.  Adenovirus‐mediated VEGF‐A gene transfer induces bone formation in vivo , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[119]  J. Wang,et al.  The angiogenic response to skeletal injury is preserved in the elderly , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

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

[121]  M. Hurley,et al.  Basic fibroblast growth factor induces osteoclast formation in murine bone marrow cultures. , 1998, Bone.

[122]  S. Rodan,et al.  Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. , 1994, The Journal of clinical investigation.

[123]  K. Miyazono,et al.  Growth/differentiation factor-5 induces angiogenesis in vivo. , 1997, Experimental cell research.

[124]  V. Rosen,et al.  The effects of aging on the bone inductive activity of recombinant human bone morphogenetic protein-2. , 1996, Endocrinology.

[125]  W Eisenmenger,et al.  Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. , 1987, Bone.

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

[127]  John C. Lee,et al.  Osteogenic protein-1 increases gene expression of vascular endothelial growth factor in primary cultures of fetal rat calvaria cells , 1999, Molecular and Cellular Endocrinology.

[128]  T. Wronski,et al.  Bone Anabolic Effects of Basic Fibroblast Growth Factor in Ovariectomized Rats* , 2022 .

[129]  K. Miwa,et al.  Local administration of activin promotes fracture healing in the rat fibula fracture model. , 1999, Bone.

[130]  R. Cancedda,et al.  Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation. , 2000, Journal of cell science.

[131]  Thomas A Einhorn,et al.  Fracture healing as a post‐natal developmental process: Molecular, spatial, and temporal aspects of its regulation , 2003, Journal of cellular biochemistry.

[132]  P. Gullino,et al.  Role of prostaglandin E1 and copper in angiogenesis. , 1982, Journal of the National Cancer Institute.

[133]  S. Furner,et al.  Musculoskeletal Conditions in the United States , 1992 .

[134]  T. White,et al.  Stratigraphic, chronological and behavioural contexts of Pleistocene Homo sapiens from Middle Awash, Ethiopia , 2003, Nature.

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

[136]  M. Klagsbrun The fibroblast growth factor family: structural and biological properties. , 1989, Progress in growth factor research.

[137]  F. Rauch,et al.  Bone morphogenetic proteins in orthopedics: from basic science to clinical practice. , 1999, Orthopedics.

[138]  S. Cook,et al.  The effect of recombinant human osteogenic protein-1 on healing of large segmental bone defects. , 1994, The Journal of bone and joint surgery. American volume.

[139]  Thiennu H. Vu,et al.  Matrix Metalloproteinase 9 and Vascular Endothelial Growth Factor Are Essential for Osteoclast Recruitment into Developing Long Bones , 2000, The Journal of cell biology.

[140]  K. Claffey,et al.  Fibroblast Growth Factor 2 Activation of Stromal Cell Vascular Endothelial Growth Factor Expression and Angiogenesis , 2001, Laboratory Investigation.

[141]  H. Redmond,et al.  Multiple angiogenic cytokines protect against osteoblast apoptosis , 2000 .

[142]  N. Ferrara,et al.  Angiogenesis and bone growth. , 2000, Trends in cardiovascular medicine.

[143]  G. Zych,et al.  Osteogenic Protein-1 (Bone Morphogenetic Protein-7) in the Treatment of Tibial Nonunions: A Prospective, Randomized Clinical Trial Comparing rhOP-1 with Fresh Bone Autograft* , 2001, The Journal of bone and joint surgery. American volume.

[144]  J. Kinney,et al.  Basic fibroblast growth factor forms new trabeculae that physically connect with pre-existing trabeculae, and this new bone is maintained with an anti-resorptive agent and enhanced with an anabolic agent in an osteopenic rat model , 2003, Osteoporosis International.

[145]  M. Devidas,et al.  The immune microenvironment of human fracture/soft-tissue hematomas and its relationship to systemic immunity. , 1997, The Journal of trauma.

[146]  H. Winet,et al.  A control model for tibial cortex neovascularization in the bone chamber , 1990, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[147]  J. Aronson Experimental and clinical experience with distraction osteogenesis. , 1994, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

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