Regulation of angiogenesis and bone regeneration with natural and synthetic small molecules

Current Pharmaceutical Design

Volumn 19, Issue 19, 2013, Pages 3403-3419

  Segar, Claire E ^a   Ogle, Molly E ^a   Botchwey, Edward A ^a  

^a Emory University   (United States)

Author keywords

Angiogenesis; Osteogenesis; Regenerative medicine; Small molecules

Indexed keywords

4 (2,6 DICHLORO 4 PYRIDINYL) 1 (1,3 DIMETHYL 4 ISOPROPYL 1H PYRAZOLO[3,4 B]PYRIDIN 6 YL)SEMICARBAZIDE; ADENOSINE; ANGIOGENESIS MODULATOR; BETA CATENIN; BIOMATERIAL; ENDOTHELIAL NITRIC OXIDE SYNTHASE; FINGOLIMOD; FRIZZLED PROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; LYSOPHOSPHATIDIC ACID; PLERIXAFOR; SEW 2971; SPHINGOSINE 1 PHOSPHATE; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 1; VCP 01091; BIOLOGICAL PRODUCT;

ANGIOGENESIS; BIOMEDICAL ENGINEERING; BLOOD VESSEL TONE; BONE DEVELOPMENT; BONE INJURY; BONE MASS; BONE REGENERATION; BONE REMODELING; CELL FUNCTION; CELL METABOLISM; CELL PROLIFERATION; CELL SURVIVAL; DISTRACTION OSTEOGENESIS; ENDOTHELIUM CELL; FRACTURE HEALING; HEMATOPOIETIC STEM CELL; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INTRACELLULAR SIGNALING; LYMPHOCYTE HOMING; MOLECULE; NONHUMAN; OSSIFICATION; OSTEOBLAST; OSTEOCLASTOGENESIS; OSTEOLYSIS; PARACRINE SIGNALING; PRIORITY JOURNAL; REGENERATIVE MEDICINE; REVIEW; STEM CELL MOBILIZATION; TRABECULAR BONE; VASCULARIZATION; ANIMAL; BONE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECT; FRACTURE; MOLECULAR LIBRARY; MUSCULOSKELETAL DISEASE;

ANIMALS; BIOLOGICAL AGENTS; BONE AND BONES; BONE REGENERATION; FRACTURES, BONE; HUMANS; MOLECULAR STRUCTURE; MUSCULOSKELETAL DISEASES; NEOVASCULARIZATION, PHYSIOLOGIC; OSTEOGENESIS; SMALL MOLECULE LIBRARIES;

EID: 84880806595     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612811319190007     Document Type: Review

References (240)

1. Haralson R ZJD. PRevalence, health care expenditures, and orthopedic surgery workforce for musculoskeletal conditions. JAMA: J the American Medical Association 2009; 302: 1586-7.
2. Lee K, Silva EA, Mooney DJ. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J R Soc Interface 2011; 8: 153-70.
3. Brownlow HC, Reed A, Simpson AH. The vascularity of atrophic non-unions. Injury 2002; 33: 145-50.
4. Lu JM, Wang X, Marin-Muller C, et al. Current advances in research and clinical applications of PLGA-based nanotechnology. Expert Rev Mol Diagn 2009; 9: 325-41.
5. Jaeblon T. Polymethylmethacrylate: properties and contemporary uses in orthopaedics. J Am Acad Orthop Surg 2010; 18: 297-305.
6. Neal RA, McClugage SG, Link MC, et al. Laminin nanofiber meshes that mimic morphological properties and bioactivity of basement membranes. Tissue Eng Part C Methods 2009; 15: 11-21.
7. Sefcik LS, Petrie Aronin CE, Wieghaus KA, et al. Sustained release of sphingosine 1-phosphate for therapeutic arteriogenesis and bone tissue engineering. Biomaterials 2008; 29: 2869-77.
8. McLaughlin SW, Cui Z, Starnes T, et al. Injectable thermogelling chitosan for the local delivery of bone morphogenetic protein. J Mater Sci Mater Med 2012
9. Kasten P, Luginbühl R, van Griensven M, et al. Comparison of human bone marrow stromal cells seeded on calcium-deficient hydroxyapatite, β-tricalcium phosphate and demineralized bone matrix. Biomaterials 2003; 24: 2593-603.
10. Ohgushi H, Okumura M, Tamai S, et al. Marrow cell induced osteogenesis in porous hydroxyapatite and tricalcium phosphate: a comparative histomorphometric study of ectopic bone formation. J Biomed Mater Res 1990; 24: 1563-70.
11. Szpalski C, Nguyen PD, Cretiu Vasiliu CE, et al. Bony engineering using time-release porous scaffolds to provide sustained growth factor delivery. J Craniofac Surg 2012; 23: 638-44.
12. Szpalski C, Wetterau M, Barr J, et al. Bone tissue engineering: current strategies and techniques-part I: scaffolds. Tissue Eng Part B Rev 2012; 18: 246-57.
13. Rezwan K, Chen QZ, Blaker JJ, et al. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials 2006; 27: 3413-31.
14. Dickson K, Katzman S, Delgado E, et al. Delayed unions and nonunions of open tibial fractures. Correlation with arteriography results. Clin Orthop Relat Res 1994: 189-93.
15. Das A, Botchwey E. Evaluation of angiogenesis and osteogenesis. Tissue Eng Part B Rev 2011; 17: 403-14.
16. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439-42.
17. Zelzer E, McLean W, Ng YS, et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 2002; 129: 1893-904.
18. Niida S, Kaku M, Amano H, et al. Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. J experimental medicine 1999; 190: 293-8.
19. Niida S, Kondo T, Hiratsuka S, et al. VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 2005; 102: 14016-21.
20. Street J, Bao M, deGuzman L, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proceedings of the National Academy of Sciences of the United States of America 2002; 99: 9656-61.
21. Wang DS, Yamazaki K, Nohtomi K, et al. Increase of vascular endothelial growth factor mRNA expression by 1,25-dihydroxyvitamin D3 in human osteoblast-like cells. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 1996; 11: 472-9.
22. Deckers MM, Karperien M, van der Bent C, et al. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology 2000; 141: 1667-74.
23. Midy V, Plouet J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem Biophys Res Commun 1994; 199: 380-6.
24. Mayr-Wohlfart U, Waltenberger J, Hausser H, et al. Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone 2002; 30: 472-7.
25. Nakagawa M, Kaneda T, Arakawa T, et al. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS letters 2000; 473: 161-4.
26. Bouletreau PJ, Warren SM, Spector JA, et al. Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. Plast Reconstr Surg 2002; 109: 2384-97.
27. Uchida S, Sakai A, Kudo H, 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. Bone 2003; 32: 491-501.
28. Yatomi Y, Ozaki Y, Ohmori T, et al. Sphingosine 1-phosphate: synthesis and release. Prostaglandins 2001; 64: 107-22.
29. Kimura T, Watanabe T, Sato K, et al. Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3. Biochem J 2000; 348 Pt 1: 71-6.
30. Lee MJ, Thangada S, Paik JH, et al. Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol Cell 2001; 8: 693-704.
31. Grey A, Chen Q, Callon K, et al. The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. Endocrinology 2002; 143: 4755-63.
32. Lee MJ, Thangada S, Claffey KP, et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 1999; 99: 301-12.
33. Liu Y, Wada R, Yamashita T, et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J clinical investigation 2000; 106: 951-61.
34. Camerer E, Regard JB, Cornelissen I, et al. Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J clinical investigation 2009; 119: 1871-9.
35. Ishii M, Egen JG, Klauschen F, et al. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 2009; 458: 524-8.
36. Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005; 23: 127-59.
37. Liu G, Yang K, Burns S, et al. The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat Immunol 2010; 11: 1047-56.
38. Ratajczak MZ, Lee H, Wysoczynski M, et al. Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia 2010; 24: 976-85.
39. Hait NC, Oskeritzian CA, Paugh SW, et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta 2006; 1758: 2016-26.
40. Kono M, Mi Y, Liu Y, et al. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biological Chem 2004; 279: 29367-73.
41. Sanchez T, Hla T. Structural and functional characteristics of S1P receptors. J Cellular Biochem 2004; 92: 913-22.
42. Lee MJ, Evans M, Hla T. The inducible G protein-coupled receptor edg-1 signals via the G(i)/mitogen-activated protein kinase pathway. J Biological Chem 1996; 271: 11272-9.
43. Ancellin N, Hla T. Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. J Biological Chem 1999; 274: 18997-9002.
44. Malek RL, Toman RE, Edsall LC, et al. Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosine-1-phosphate receptors. J Biological Chem 2001; 276: 5692-9.
45. Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010; 9: 883-97.
46. Allende ML, Yamashita T, Proia RL. G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 2003; 102: 3665-7.
47. MacLennan AJ, Carney PR, Zhu WJ, et al. An essential role for the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate receptor in neuronal excitability. Eur J Neurosci 2001; 14: 203-9.
48. Kono M, Belyantseva IA, Skoura A, et al. Deafness and stria vascularis defects in S1P2 receptor-null mice. J Biological Chem 2007; 282: 10690-6.
49. Ishii I, Friedman B, Ye X, et al. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3. J Biological Chem 2001; 276: 33697-704.
50. Jaillard C, Harrison S, Stankoff B, et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 2005; 25: 1459-69.
51. Golfier S, Kondo S, Schulze T, et al. Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P4. FASEB J 2010; 24: 4701-10.
52. Oyama O, Sugimoto N, Qi X, et al. The lysophospholipid mediator sphingosine-1-phosphate promotes angiogenesis in vivo in ischaemic hindlimbs of mice. Cardiovasc Res 2008; 78: 301-7.
53. Walter DH, Rochwalsky U, Reinhold J, et al. Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler Thromb Vasc Biol 2007; 27: 275-82.
54. Wamhoff BR, Lynch KR, Macdonald TL, et al. Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 2008; 28: 1454-61.
55. Wacker BK, Scott EA, Kaneda MM, et al. Delivery of sphingosine 1-phosphate from poly(ethylene glycol) hydrogels. Biomacromolecules 2006; 7: 1335-43.
56. Scott EA, Nichols MD, Kuntz-Willits R, et al. Modular scaffolds assembled around living cells using poly(ethylene glycol) microspheres with macroporation via a non-cytotoxic porogen. Acta Biomater 2010; 6: 29-38.
57. Qi X, Okamoto Y, Murakawa T, et al. Sustained delivery of sphingosine-1-phosphate using poly(lactic-co-glycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice. Eur J Pharmacol 2010; 634: 121-31.
58. Petrie Aronin CE, Sefcik LS, Tholpady SS, et al. FTY720 promotes local microvascular network formation and regeneration of cranial bone defects. Tissue Eng Part A 2010; 16: 1801-9.
59. Sefcik LS, Aronin CE, Awojoodu AO, et al. Selective activation of sphingosine 1-phosphate receptors 1 and 3 promotes local microvascular network growth. Tissue Eng Part A 2011; 17: 617-29.
60. Kovarik JM, Schmouder R, Barilla D, et al. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol 2004; 57: 586-91.
61. Saba JD, Hla T. Point-counterpoint of sphingosine 1-phosphate metabolism. Circ Res 2004; 94: 724-34.
62. Petrie Aronin CE, Shin SJ, Naden KB, et al. The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720. Biomaterials 2010; 31: 6417-24.
63. Huang C, Das A, Barker D, et al. Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation. Cell Tissue Res 2012; 347: 553-66.
64. Sato C, Iwasaki T, Kitano S, et al. Sphingosine 1-phosphate receptor activation enhances BMP-2-induced osteoblast differentiation. Biochem Biophysical Res Communications 2012; 423: 200-5.
65. Ryu J, Kim HJ, Chang EJ, et al. Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO Journal 2006; 25: 5840-51.
66. Chiba K, Yanagawa Y, Masubuchi Y, et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 1998; 160: 5037-44.
67. Kimura T, Boehmler AM, Seitz G, et al. The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells. Blood 2004; 103: 4478-86.
68. Golan K, Vagima Y, Ludin A, et al. S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release. Blood 2012; 119: 2478-88.
69. Ryser MF, Ugarte F, Lehmann R, et al. S1P(1) overexpression stimulates S1P-dependent chemotaxis of human CD34+ hematopoietic progenitor cells but strongly inhibits SDF-1/CXCR4-dependent migration and in vivo homing. Mol Immunol 2008; 46: 166-71.
70. Juarez JG, Harun N, Thien M, et al. Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice. Blood 2012; 119: 707-16.
71. Tokumura A, Majima E, Kariya Y, et al. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biological Chem 2002; 277: 39436-42.
72. Choi JW, Herr DR, Noguchi K, et al. LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol 2010; 50: 157-86.
73. van Meeteren LA, Ruurs P, Stortelers C, et al. Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol Cell Biol 2006; 26: 5015-22.
74. Tanaka M, Okudaira S, Kishi Y, et al. Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J Biological Chem 2006; 281: 25822-30.
75. Rivera-Lopez CM, Tucker AL, Lynch KR. Lysophosphatidic acid (LPA) and angiogenesis. Angiogenesis 2008; 11: 301-10.
76. Lin CI, Chen CN, Huang MT, et al. Lysophosphatidic acid upregulates vascular endothelial growth factor-C and tube formation in human endothelial cells through LPA(1/3), COX-2, and NF-kappaB activation-and EGFR transactivation-dependent mechanisms. Cell Signal 2008; 20: 1804-14.
77. Ren B, Hale J, Srikanthan S, et al. Lysophosphatidic acid suppresses endothelial cell CD36 expression and promotes angiogenesis via a PKD-1-dependent signaling pathway. Blood 2011; 117: 6036-45.
78. Kimura T, Mogi C, Sato K, et al. p2y5/LPA(6) attenuates LPA(1)-mediated VE-cadherin translocation and cell-cell dissociation through G(12/13) protein-Src-Rap1. Cardiovasc Res 2011; 92: 149-58.
79. Subramanian P, Karshovska E, Reinhard P, et al. Lysophosphatidic acid receptors LPA1 and LPA3 promote CXCL12-mediated smooth muscle progenitor cell recruitment in neointima formation. Circ Res 2010; 107: 96-105.
80. Blackburn J, Mansell JP. The emerging role of lysophosphatidic acid (LPA) in skeletal biology. Bone 2012; 50: 756-62.
81. Grey A, Banovic T, Naot D, et al. Lysophosphatidic acid is an osteoblast mitogen whose proliferative actions involve G(i) proteins and protein kinase C, but not P42/44 mitogen-activated protein kinases. Endocrinology 2001; 142: 1098-106.
82. Masiello LM, Fotos JS, Galileo DS, et al. Lysophosphatidic acid induces chemotaxis in MC3T3-E1 osteoblastic cells. Bone 2006; 39: 72-82.
83. Gidley J, Openshaw S, Pring ET, et al. Lysophosphatidic acid cooperates with 1alpha,25(OH)2D3 in stimulating human MG63 osteoblast maturation. Prostaglandins Other Lipid Mediat 2006; 80: 46-61.
84. Mansell JP, Blackburn J. Lysophosphatidic acid, human osteoblast formation, maturation and the role of 1alpha,25-Dihydroxyvitamin D3 (calcitriol). Biochimica et biophysica acta 2012
85. Liu YB, Kharode Y, Bodine PV, et al. LPA induces osteoblast differentiation through interplay of two receptors: LPA1 and LPA4. J Cell Biochem 2010; 109: 794-800.
86. Waters KM, Tan R, Genetos DC, et al. DNA microarray analysis reveals a role for lysophosphatidic acid in the regulation of antiinflammatory genes in MC3T3-E1 cells. Bone 2007; 41: 833-41.
87. Gennero I, Laurencin-Dalicieux S, Conte-Auriol F, et al. Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass. Bone 2011; 49: 395-403.
88. Sims SM, Panupinthu N, Lapierre DM, et al. Lysophosphatidic acid: A potential mediator of osteoblast-osteoclast signaling in bone. Biochimica et Biophysica Acta 2013; 1831: 109-16.
89. Lapierre DM, Tanabe N, Pereverzev A, et al. Lysophosphatidic acid signals through multiple receptors in osteoclasts to elevate cytosolic calcium concentration, evoke retraction, and promote cell survival. J Biological Chem 2010; 285: 25792-801.
90. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701-5.
91. Liu F, Poursine-Laurent J, Link DC. Expression of the G-CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G-CSF. Blood 2000; 95: 3025-31.
92. Kim HK, De La Luz Sierra M, Williams CK, et al. G-CSF downregulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells. Blood 2006; 108: 812-20.
93. Lichterfeld M, Martin S, Burkly L, et al. Mobilization of CD34+ haematopoietic stem cells is associated with a functional inactivation of the integrin very late antigen 4. Br J Haematol 2000; 110: 71-81.
94. Winkler IG, Sims NA, Pettit AR, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 2010; 116: 4815-28.
95. Chow A, Lucas D, Hidalgo A, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Experimental Med 2011; 208: 261-71.
96. Christopher MJ, Rao M, Liu F, et al. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J Experimental Med 2011; 208: 251-60.
97. Semerad CL, Christopher MJ, Liu F, et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 2005; 106: 3020-7.
98. Honold J, Lehmann R, Heeschen C, et al. Effects of granulocyte colony simulating factor on functional activities of endothelial progenitor cells in patients with chronic ischemic heart disease. Arterioscler Thromb Vasc Biol 2006; 26: 2238-43.
99. Brunner S, Huber BC, Fischer R, et al. G-CSF treatment after myocardial infarction: impact on bone marrow-derived vs cardiac progenitor cells. Exp Hematol 2008; 36: 695-702.
100. Rettig MP, Ansstas G, DiPersio JF. Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4. Leukemia 2012; 26: 34-53.
101. Priestley GV, Ulyanova T, Papayannopoulou T. Sustained alterations in biodistribution of stem/progenitor cells in Tie2Cre+ alpha4(f/f) mice are hematopoietic cell autonomous. Blood 2007; 109: 109-11.
102. Shepherd RM, Capoccia BJ, Devine SM, et al. Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100. Blood 2006; 108: 3662-7.
103. Jujo K, Hamada H, Iwakura A, et al. CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction. Proc Natl Acad Sci USA 2010; 107: 11008-13.
104. Capoccia BJ, Shepherd RM, Link DC. G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. Blood 2006; 108: 2438-45.
105. Liu L, Hu K, Wang B, et al. Mobilization of endogenous stem cells: A new strategy for bone healing. Bone 2012; 51: 633-4.
106. Kitaori T, Ito H, Schwarz EM, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheumatism 2009; 60: 813-23.
107. Christopher MJ, Link DC. Granulocyte colony-stimulating factor induces osteoblast apoptosis and inhibits osteoblast differentiation. Journal of bone and mineral research: the official J Am Soc Bone Mineral Res 2008; 23: 1765-74.
108. Singh P, Hu P, Hoggatt J, et al. Expansion of bone marrow neutrophils following G-CSF administration in mice results in osteolineage cell apoptosis and mobilization of hematopoietic stem and progenitor cells. Leukemia 2012
109. Wang XX, Allen RJ, Jr., Tutela JP, et al. Progenitor cell mobilization enhances bone healing by means of improved neovascularization and osteogenesis. Plast Reconstr Surg 2011; 128: 395-405.
110. Kumar S, Ponnazhagan S. Mobilization of bone marrow mesenchymal stem cells in vivo augments bone healing in a mouse model of segmental bone defect. Bone 2012; 50: 1012-8.
111. Wise JK, Sumner DR, Virdi AS. Modulation of stromal cellderived factor-1/CXC chemokine receptor 4 axis enhances rhBMP-2-induced ectopic bone formation. Tissue Eng Part A 2012; 18: 860-9.
112. Harris SG, Padilla J, Koumas L, et al. Prostaglandins as modulators of immunity. Trends Immunol 2002; 23: 144-50.
113. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 2004; 103: 147-66.
114. Gelse K, Beyer C. The prostaglandin E(2) system: a toolbox for skeletal repair? Arthritis Rheumatism 2011; 63: 871-3.
115. Form DM, Auerbach R. PGE2 and angiogenesis. Proc Soc Exp Biol Med 1983; 172: 214-8.
116. Namkoong S, Lee SJ, Kim CK, et al. Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells. Exp Mol Med 2005; 37: 588-600.
117. Rao R, Redha R, Macias-Perez I, et al. Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo. J Biol Chem 2007; 282: 16959-68.
118. Hoggatt J, Singh P, Sampath J, et al. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 2009; 113: 5444-55.
119. Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone: bad cop, good cop? Trends Endocrinol Metabolism: TEM 2010; 21: 294-301.
120. Harada S, Nagy JA, Sullivan KA, et al. Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J clinical investigation 1994; 93: 2490-6.
121. Kobayashi Y, Mizoguchi T, Take I, et al. Prostaglandin E2 enhances osteoclastic differentiation of precursor cells through protein kinase A-dependent phosphorylation of TAK1. J Biological Chem 2005; 280: 11395-403.
122. Take I, Kobayashi Y, Yamamoto Y, et al. Prostaglandin E2 strongly inhibits human osteoclast formation. Endocrinology 2005; 146: 5204-14.
123. Ono K, Kaneko H, Choudhary S, et al. Biphasic effect of prostaglandin E2 on osteoclast formation in spleen cell cultures: role of the EP2 receptor. Journal of bone and mineral research: the official J Am Soc Bone Mineral Res 2005; 20: 23-9.
124. Keila S, Kelner A, Weinreb M. Systemic prostaglandin E2 increases cancellous bone formation and mass in aging rats and stimulates their bone marrow osteogenic capacity in vivo and in vitro. J Endocrinol 2001; 168: 131-9.
125. Machwate M, Harada S, Leu CT, et al. Prostaglandin receptor EP(4) mediates the bone anabolic effects of PGE(2). Molecular pharmacology 2001; 60: 36-41.
126. Kato N, Hasegawa U, Morimoto N, et al. Nanogel-based delivery system enhances PGE2 effects on bone formation. J Cellular Biochem 2007; 101: 1063-70.
127. Tanaka M, Sakai A, Uchida S, et al. Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819. CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats. Bone 2004; 34: 940-8.
128. Zhang X, Schwarz EM, Young DA, et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J clinical Investigation 2002; 109: 1405-15.
129. Chikazu D, Li X, Kawaguchi H, et al. Bone morphogenetic protein 2 induces cyclo-oxygenase 2 in osteoblasts via a Cbfal binding site: role in effects of bone morphogenetic protein 2 in vitro and in vivo. Journal of bone and mineral research: the official J Am Soc Bone Mineral Res 2002; 17: 1430-40.
130. Yoon DS, Yoo JH, Kim YH, et al. The effects of COX-2 inhibitor during osteogenic differentiation of bone marrow-derived human mesenchymal stem cells. Stem Cells Dev 2010; 19: 1523-33.
131. Toyoda H, Terai H, Sasaoka R, et al. Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist. Bone 2005; 37: 555-62.
132. Kamolratanakul P, Hayata T, Ezura Y, et al. Nanogel-based scaffold delivery of prostaglandin E(2) receptor-specific agonist in combination with a low dose of growth factor heals critical-size bone defects in mice. Arthritis Rheumatism 2011; 63: 1021-33.
133. Nakagawa K, Imai Y, Ohta Y, et al. Prostaglandin E2 EP4 agonist (ONO-4819) accelerates BMP-induced osteoblastic differentiation. Bone 2007; 41: 543-8.
134. Fredholm BB. Adenosine receptors as drug targets. Exp Cell Res 2010; 316: 1284-8.
135. Dusseau JW, Hutchins PM, Malbasa DS. Stimulation of angiogenesis by adenosine on the chick chorioallantoic membrane. Circ Res 1986; 59: 163-70.
136. Ryzhov S, McCaleb JL, Goldstein AE, et al. Role of adenosine receptors in the regulation of angiogenic factors and neovascularization in hypoxia. J Pharmacol Exp Ther 2007; 320: 565-72.
137. Yang D, Koupenova M, McCrann DJ, et al. The A2b adenosine receptor protects against vascular injury. Proc Natl Acad Sci USA 2008; 105: 792-6.
138. Feoktistov I, Goldstein AE, Ryzhov S, et al. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res 2002; 90: 531-8.
139. Montesinos MC, Shaw JP, Yee H, et al. Adenosine A(2A) receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. Am J Pathol 2004; 164: 1887-92.
140. Leibovich SJ, Chen JF, Pinhal-Enfield G, et al. Synergistic upregulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Am J Pathol 2002; 160: 2231-44.
141. Ernens I, Leonard F, Vausort M, et al. Adenosine up-regulates vascular endothelial growth factor in human macrophages. Biochemical Biophysical Res Communications 2010; 392: 351-6.
142. Clark AN, Youkey R, Liu X, et al. A1 adenosine receptor activation promotes angiogenesis and release of VEGF from monocytes. Circ Res 2007; 101: 1130-8.
143. Feoktistov I, Ryzhov S, Goldstein AE, et al. Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res 2003; 92: 485-92.
144. Costa MA, Barbosa A, Neto E, et al. On the role of subtype selective adenosine receptor agonists during proliferation and osteogenic differentiation of human primary bone marrow stromal cells. J Cell Physiol 2011; 226: 1353-66.
145. Carroll SH, Wigner NA, Kulkarni N, et al. A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J Biological Chem 2012; 287: 15718-27.
146. Kara FM, Chitu V, Sloane J, et al. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. FASEB J 2010; 24: 2325-33.
147. Mediero A, Kara FM, Wilder T, et al. Adenosine A(2A) receptor ligation inhibits osteoclast formation. Am J Pathol 2012; 180: 775-86.
148. Sugama R, Koike T, Imai Y, et al. Bone morphogenetic protein activities are enhanced by 3',5'-cyclic adenosine monophosphate through suppression of Smad6 expression in osteoprogenitor cells. Bone 2006; 38: 206-14.
149. Siddappa R, Martens A, Doorn J, et al. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. Proc Natl Acad Sci USA 2008; 105: 7281-6.
150. Doorn J, van de Peppel J, van Leeuwen JP, et al. Pro-osteogenic trophic effects by PKA activation in human mesenchymal stromal cells. Biomaterials 2011; 32: 6089-98.
151. Lo KW, Kan HM, Ashe KM, et al. The small molecule PKAspecific cyclic AMP analogue as an inducer of osteoblast-like cells differentiation and mineralization. J Tissue Eng Regen Med 2012; 6: 40-8.
152. Sugiyama M, Kodama T, Konishi K, et al. Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells. Biochemical Biophysical Res Communications 2000; 271: 688-92.
153. Maeda T, Kawane T, Horiuchi N. Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. Endocrinology 2003; 144: 681-92.
154. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999; 286: 1946-9.
155. Song C, Guo Z, Ma Q, et al. Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells. Biochemical Biophysical Res Communications 2003; 308: 458-62.
156. Ruiz-Gaspa S, Nogues X, Enjuanes A, et al. Simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG-63 cultures. J Cellular Biochem 2007; 101: 1430-8.
157. Takenaka M, Hirade K, Tanabe K, et al. Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells. Biochemical Biophysical Res communications 2003; 301: 198-203.
158. Staal A, Frith JC, French MH, et al. The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. Journal of bone and mineral research: the official J Am Soc Bone Mineral Res 2003; 18: 88-96.
159. Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA 1999; 96: 133-8.
160. Ohno T, Shigetomi M, Ihara K, et al. Skeletal reconstruction by vascularized allogenic bone transplantation: effects of statin in rats. Transplantation 2003; 76: 869-71.
161. Rojbani H, Nyan M, Ohya K, et al. Evaluation of the osteoconductivity of alpha-tricalcium phosphate, beta-tricalcium phosphate, and hydroxyapatite combined with or without simvastatin in rat calvarial defect. J Biomed Mater Res A 2011; 98: 488-98.
162. Nyan M, Miyahara T, Noritake K, et al. Molecular and tissue responses in the healing of rat calvarial defects after local application of simvastatin combined with alpha tricalcium phosphate. J Biomed Mater Res B Appl Biomater 2010; 93: 65-73.
163. Ozec I, Kilic E, Gumus C, et al. Effect of local simvastatin application on mandibular defects. J Craniofac Surg 2007; 18: 546-50.
164. Ho MH, Chiang CP, Liu YF, et al. Highly efficient release of lovastatin from poly(lactic-co-glycolic acid) nanoparticles enhances bone repair in rats. J Orthop Res 2011; 29: 1504-10.
165. Yoshii T, Hafeman AE, Esparza JM, et al. Local injection of lovastatin in biodegradable polyurethane scaffolds enhances bone regeneration in a critical-sized segmental defect in rat femora. J Tissue Eng Regen Med 2012
166. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow--derived endothelial progenitor cells. J Clinical Investigation 2001; 108: 399-405.
167. Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clinical Investigation 2001; 108: 391-7.
168. Walter DH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002; 105: 3017-24.
169. Shao H, Tan Y, Eton D, et al. Statin and stromal cell-derived factor-1 additively promote angiogenesis by enhancement of progenitor cells incorporation into new vessels. Stem Cells 2008; 26: 1376-84.
170. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996; 16: 4604-13.
171. Semenza GL, Roth PH, Fang HM, et al. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 1994; 269: 23757-63.
172. Zaman K, Ryu H, Hall D, et al. Protection from Oxidative Stress-Induced Apoptosis in Cortical Neuronal Cultures by Iron Chelators Is Associated with Enhanced DNA Binding of Hypoxia-Inducible Factor-1 and ATF-1/CREB and Increased Expression of Glycolytic Enzymes, p21waf1/cip1, and Erythropoietin. J Neurosci 1999; 19: 9821-30.
173. Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 1993; 82: 3610-5.
174. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biological Chem 1995; 270: 1230-7.
175. Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 2000; 35: 71-103.
176. Jiang BH, Semenza GL, Bauer C, et al. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 1996; 271: C1172-80.
177. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294: 1337-40.
178. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292: 468-72.
179. Semenza GL. Physiology meets biophysics: visualizing the interaction of hypoxia-inducible factor 1 alpha with p300 and CBP. Proc Natl Acad Sci USA 2002; 99: 11570-2.
180. Iyer NV, Kotch LE, Agani F, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Development 1998; 12: 149-62.
181. Kotch LE, Iyer NV, Laughner E, et al. Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Developmental Biol 1999; 209: 254-67.
182. Wan C, Gilbert SR, Wang Y, et al. Activation of the hypoxiainducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci USA 2008; 105: 686-91.
183. Semenza GL. HIF-1: using two hands to flip the angiogenic switch. Cancer Metastasis Rev 2000; 19: 59-65.
184. Han Y, Kuang SZ, Gomer A, et al. Hypoxia influences the vascular expansion and differentiation of embryonic stem cell cultures through the temporal expression of vascular endothelial growth factor receptors in an ARNT-dependent manner. Stem Cells 2010; 28: 799-809.
185. Coulet F, Nadaud S, Agrapart M, et al. Identification of hypoxiaresponse element in the human endothelial nitric-oxide synthase gene promoter. J Biological Chem 2003; 278: 46230-40.
186. Synnestvedt K, Furuta GT, Comerford KM, et al. Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clinical Investigation 2002; 110: 993-1002.
187. Hart ML, Grenz A, Gorzolla IC, et al. Hypoxia-inducible factor-1alpha-dependent protection from intestinal ischemia/reperfusion injury involves ecto-5'-nucleotidase (CD73) and the A2B adenosine receptor. J Immunology 2011; 186: 4367-74.
188. Wang Y, Wan C, Deng L, et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest 2007; 117: 1616-26.
189. Rankin EB, Wu C, Khatri R, et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 2012; 149: 63-74.
190. Schipani E, Ryan HE, Didrickson S, et al. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes & development 2001; 15: 2865-76.
191. Arnett TR, Gibbons DC, Utting JC, et al. Hypoxia is a major stimulator of osteoclast formation and bone resorption. J Cell Physiol 2003; 196: 2-8.
192. Knowles HJ, Cleton-Jansen AM, Korsching E, et al. Hypoxiainducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4. FASEB J 2010; 24: 4648-59.
193. Leger AJ, Altobelli A, Mosquea LM, et al. Inhibition of osteoclastogenesis by prolyl hydroxylase inhibitor dimethyloxallyl glycine. J Bone Miner Metab 2010; 28: 510-9.
194. Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007; 39: 231-4.
195. Elvidge GP, Glenny L, Appelhoff RJ, et al. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. J Biol Chem 2006; 281: 15215-26.
196. Warnecke C, Griethe W, Weidemann A, et al. Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J 2003; 17: 1186-8.
197. Liu J, Tang T, Yang H. Protective effect of deferoxamine on experimental spinal cord injury in rat. Injury 2011; 42: 742-5.
198. Ikeda Y, Tajima S, Yoshida S, et al. Deferoxamine promotes angiogenesis via the activation of vascular endothelial cell function. Atherosclerosis 2011; 215: 339-47.
199. Shen X, Wan C, Ramaswamy G, et al. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J Orthop Res 2009; 27: 1298-305.
200. Ivan M, Haberberger T, Gervasi DC, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Nat Acad Sci USA 2002; 99: 13459-64.
201. Donneys A, Farberg AS, Tchanque-Fossuo CN, et al. Deferoxamine enhances the vascular response of bone regeneration in mandibular distraction osteogenesis. Plastic Reconstructive Surgery 2012; 129: 850-6.
202. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 2012; 149: 1192-205.
203. Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proce Natl Acad Sci USA 2005; 102: 3324-9.
204. Kubota T, Michigami T, Sakaguchi N, et al. Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. Journal of bone and mineral research: the official J Am Soc Bone Mineral Res 2008; 23: 1661-71.
205. Bodine PV, Billiard J, Moran RA, et al. The Wnt antagonist secreted frizzled-related protein-1 controls osteoblast and osteocyte apoptosis. J Cellular Biochem 2005; 96: 1212-30.
206. Daneman R, Agalliu D, Zhou L, et al. Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci USA 2009; 106: 641-6.
207. Kulkarni NH, Onyia JE, Zeng Q, et al. Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo. Journal of bone and mineral research: the official J Am Soc Bone Mineral Res 2006; 21: 910-20.
208. Marsell R, Sisask G, Nilsson Y, et al. GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone 2012; 50: 619-27.
209. Zhou F, Huang H, Zhang L. Bisindoylmaleimide I enhances osteogenic differentiation. Protein Cell 2012; 3: 311-20.
210. Bodine PV, Stauffer B, Ponce-de-Leon H, et al. A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation. Bone 2009; 44: 1063-8.
211. Pelletier JC, Lundquist JTt, Gilbert AM, et al. (1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: a wingless betacatenin agonist that increases bone formation rate. J Med Chem 2009; 52: 6962-5.
212. Gwak J, Hwang SG, Park HS, et al. Small molecule-based disruption of the Axin/beta-catenin protein complex regulates mesenchymal stem cell differentiation. Cell Res 2012; 22: 237-47.
213. Yonezawa T, Lee JW, Hibino A, et al. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling. Biochemical Biophysical Res Communications 2011; 409: 260-5.
214. Higuchi C, Myoui A, Hashimoto N, et al. Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix. Journal of bone and mineral research: the official J Am Soc Bone Mineral Res 2002; 17: 1785-94.
215. Liu Z, Kobayashi K, van Dinther M, et al. VEGF and inhibitors of TGFbeta type-I receptor kinase synergistically promote bloodvessel formation by inducing alpha5-integrin expression. J Cell Sci 2009; 122: 3294-302.
216. Michaud MD, Robitaille GA, Gratton JP, et al. Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells. Arterioscler Thromb Vasc Biol 2009; 29: 902-8.
217. Ader I, Malavaud B, Cuvillier O. When the sphingosine kinase 1/sphingosine 1-phosphate pathway meets hypoxia signaling: new targets for cancer therapy. Cancer Res 2009; 69: 3723-6.
218. Herr B, Zhou J, Werno C, et al. The supernatant of apoptotic cells causes transcriptional activation of hypoxia-inducible factor-1alpha in macrophages via sphingosine-1-phosphate and transforming growth factor-beta. Blood 2009; 114: 2140-8.
219. Tanimoto T, Jin ZG, Berk BC. Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). J Biological Chem 2002; 277: 42997-3001.
220. Igarashi J, Erwin PA, Dantas AP, et al. VEGF induces S1P1 receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors. Proc Natl Acad Sci USA 2003; 100: 10664-9.
221. Brecht K, Weigert A, Hu J, et al. Macrophages programmed by apoptotic cells promote angiogenesis via prostaglandin E2. FASEB J 2011; 25: 2408-17.
222. Dragusin M, Wehner S, Kelly S, et al. Effects of sphingosine-1-phosphate and ceramide-1-phosphate on rat intestinal smooth muscle cells: implications for postoperative ileus. FASEB J 2006; 20: 1930-2.
223. Pederson L, Ruan M, Westendorf JJ, et al. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 2008; 105: 20764-9.
224. Wieghaus KA, Gianchandani EP, Paige MA, et al. Novel pathway compendium analysis elucidates mechanism of pro-angiogenic synthetic small molecule. Bioinformatics 2008; 24: 2384-90.
225. Butcher RA, Schreiber SL. Using genome-wide transcriptional profiling to elucidate small-molecule mechanism. Curr Opin Chem Biol 2005; 9: 25-30.
226. Brey DM, Motlekar NA, Diamond SL, et al. High-throughput screening of a small molecule library for promoters and inhibitors of mesenchymal stem cell osteogenic differentiation. Biotechnol Bioeng 2011; 108: 163-74.
227. Peters A, Brey DM, Burdick JA. High-throughput and combinatorial technologies for tissue engineering applications. Tissue Eng Part B Rev 2009; 15: 225-39.
228. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature Reviews Immunol 2007; 7: 292-304.
229. Vandenburgh H. High-content drug screening with engineered musculoskeletal tissues. Tissue Eng Part B Rev 2010; 16: 55-64.
230. Kluk MJ, Hla T. Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration. Circ Res 2001; 89: 496-502.
231. Butler J, Lana D, Round O, et al. Functional characterization of sphingosine 1-phosphate receptor agonist in human endothelial cells. Prostaglandins Other Lipid Mediat 2004; 73: 29-45.
232. Bowers DT, Chhabra P, Langman L, et al. FTY720-loaded poly(DL-lactide-co-glycolide) electrospun scaffold significantly increases microvessel density over 7 days in streptozotocin-induced diabetic C57b16/J mice: preliminary results. Transplant Proc 2011; 43: 3285-7.
233. Taylor PA, Kelly RM, Bade ND, et al. FTY720 Markedly Increases Alloengraftment but Does Not Eliminate Host Anti-Donor T Cells that Cause Graft Rejection on Its Withdrawal. Biol Blood Marrow Transplant 2012; 18: 1341-52.
234. Hoang MV, Nagy JA, Senger DR. Active Rac1 improves pathologic VEGF neovessel architecture and reduces vascular leak: mechanistic similarities with angiopoietin-1. Blood 2011; 117: 1751-60.
235. Osada M, Yatomi Y, Ohmori T, et al. Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist. Biochem Biophys Res Commun 2002; 299: 483-7.
236. Inoki I, Takuwa N, Sugimoto N, et al. Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor. Biochem Biophys Res Commun 2006; 346: 293-300.
237. Skoura A, Michaud J, Im DS, et al. Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31: 81-5.
238. Ishii M, Kikuta J, Shimazu Y, et al. Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med 2010; 207: 2793-8.
239. Donneys A, Tchanque-Fossuo CN, Farberg AS, et al. Bone regeneration in distraction osteogenesis demonstrates significantly increased vascularity in comparison to fracture repair in the mandible. J Craniofac Surg 2012; 23: 328-32.
240. Fan W, Crawford R, Xiao Y. Enhancing in vivo vascularized bone formation by cobalt chloride-treated bone marrow stromal cells in a tissue engineered periosteum model. Biomaterials 2010; 31: 3580-9.