BMPs and their clinical potentials

BMB Reports

Volumn 44, Issue 10, 2011, Pages 619-634

  Kim, Meejung ^a   Choe, Senyon ^a,b  

^a Gachon University College of Medicine   (South Korea)

^b SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

Author keywords

BMP; Cancer; Diabetes; Obesity; Pulmonary hypertension; TGF beta

Indexed keywords

BONE MORPHOGENETIC PROTEIN;

ANIMAL; HUMAN; METABOLIC DISORDER; NEOPLASM; PHYSIOLOGY; SHORT SURVEY; SIGNAL TRANSDUCTION; VASCULAR DISEASE;

ANIMALS; BONE MORPHOGENETIC PROTEINS; HUMANS; METABOLIC DISEASES; NEOPLASMS; SIGNAL TRANSDUCTION; VASCULAR DISEASES;

EID: 84863229795     PISSN: 19766696     EISSN: 1976670X     Source Type: Journal    
DOI: 10.5483/BMBRep.2011.44.10.619     Document Type: Short Survey

References (211)

1. Wagner, D. O., Sieber, C., Bhushan, R., Borgermann, J. H., Graf, D. and Knaus, P. (2010) BMPs: from bone to body morphogenetic proteins. Sci. Signal. 3, mr1.
2. Reddi, A. H. (2005) BMPs: from bone morphogenetic proteins to body morphogenetic proteins. Cytokine. Growth. Factor. Rev. 16, 249-250.
3. Satterfield, M. C. and Wu, G. (2011) Brown adipose tissue growth and development: significance and nutritional regulation. Front. Biosci. 16, 1589-1608.
4. Kopelman, P. G. (2000) Obesity as a medical problem. Nature 404, 635-643.
5. Hsu, I. R., Kim, S. P., Kabir, M. and Bergman, R. N. (2007) Metabolic syndrome, hyperinsulinemia, and cancer. Am J. Clin. Nutr. 86, s867-871.
6. Craft, S. (2007) Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr. Alzheimer. Res. 4, 147-152.
7. Cornier, M. A., Dabelea, D., Hernandez, T. L., Lindstrom, R. C., Steig, A. J., Stob, N. R., Van Pelt, R. E., Wang, H. and Eckel, R. H. (2008) The metabolic syndrome. Endocr. Rev. 29, 777-822.
8. Hammond, R. A. and Levine, R. (2010) The economic impact of obesity in the United States. Diabetes. Metab. Syndr. Obes. 3, 285-295.
9. Zamani, N. and Brown, C. W. (2011) Emerging roles for the transforming growth factor-{beta} superfamily in regulating adiposity and energy expenditure. Endocr. Rev. 32, 387-403.
10. Snow, V., Barry, P., Fitterman, N., Qaseem, A. and Weiss, K. (2005) Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians. Ann. Intern. Med. 142, 525-531.
11. Colman, E. (2005) Anorectics on trial: a half century of federal regulation of prescription appetite suppressants. Ann. Intern. Med. 143, 380-385.
12. Gesta, S., Tseng, Y. H. and Kahn, C. R. (2007) Developmental origin of fat: tracking obesity to its source. Cell 131, 242-256.
13. Martinsson, A. (1969) Hypertrophy and hyperplasia of human adipose tissue in obesity. Pol. Arch. Med. Wewn. 42, 481-486.
14. Shepherd, P. R., Gnudi, L., Tozzo, E., Yang, H., Leach, F. and Kahn, B. B. (1993) Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. J. Biol. Chem. 268, 22243-22246.
15. Otto, T. C. and Lane, M. D. (2005) Adipose development: from stem cell to adipocyte. Crit. Rev. Biochem. Mol. Biol. 40, 229-242.
16. Tang, Q. Q., Otto, T. C. and Lane, M. D. (2004) Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc. Natl. Acad. Sci. U.S.A. 101, 9607-9611.
17. Tseng, Y. H., Kokkotou, E., Schulz, T. J., Huang, T. L., Winnay, J. N., Taniguchi, C. M., Tran, T. T., Suzuki, R., Espinoza, D. O., Yamamoto, Y., Ahrens, M. J., Dudley, A. T., Norris, A. W., Kulkarni, R. N. and Kahn, C. R. (2008) New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 454, 1000-1004.
18. Bowers, R. R., Kim, J. W., Otto, T. C. and Lane, M. D. (2006) Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene. Proc. Natl. Acad. Sci. U.S.A. 103, 13022-13027.
19. Dani, C., Smith, A. G., Dessolin, S., Leroy, P., Staccini, L., Villageois, P., Darimont, C. and Ailhaud, G. (1997) Differentiation of embryonic stem cells into adipocytes in vitro. J. Cell. Sci. 110(Pt 11), 1279-1285.
20. Bowers, R. R. and Lane, M. D. (2007) A role for bone morphogenetic protein-4 in adipocyte development. Cell Cycle. 6, 385-389.
21. Ji, X., Chen, D., Xu, C., Harris, S. E., Mundy, G. R. and Yoneda, T. (2000) Patterns of gene expression associated with BMP-2-induced osteoblast and adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A. J. Bone Miner. Metab. 18, 132-139.
22. Sottile, V. and Seuwen, K. (2000) Bone morphogenetic protein-2 stimulates adipogenic differentiation of mesenchymal precursor cells in synergy with BRL 49653 (rosiglitazone). FEBS Lett. 475, 201-204.
23. Hata, K., Nishimura, R., Ikeda, F., Yamashita, K., Matsubara, T., Nokubi, T. and Yoneda, T. (2003) Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Mol. Biol. Cell 14, 545-555.
24. Jin, W., Takagi, T., Kanesashi, S. N., Kurahashi, T., Nomura, T., Harada, J. and Ishii, S. (2006) Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev. Cell 10, 461-471.
25. Chen, D., Ji, X., Harris, M. A., Feng, J. Q., Karsenty, G., Celeste, A. J., Rosen, V., Mundy, G. R. and Harris, S. E. (1998) Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J. Cell. Biol. 142, 295-305.
26. Sebald, W., Nickel, J., Zhang, J. L. and Mueller, T. D. (2004) Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction. Biol. Chem. 385, 697-710.
27. Schulz, T. J. and Tseng, Y. H. (2009) Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine. Growth. Factor. Rev. 20, 523-531.
28. Bottcher, Y., Unbehauen, H., Kloting, N., Ruschke, K., Korner, A., Schleinitz, D., Tonjes, A., Enigk, B., Wolf, S., Dietrich, K., Koriath, M., Scholz, G. H., Tseng, Y. H., Dietrich, A., Schon, M. R., Kiess, W., Stumvoll, M., Bluher, M. and Kovacs, P. (2009) Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity. Diabetes 58, 2119-2128.
29. Wu, Y., Zhou, S. and Smas, C. M. (2010) Downregulated expression of the secreted glycoprotein follistatin-like 1 (Fstl1) is a robust hallmark of preadipocyte to adipocyte conversion. Mech. Dev. 127, 183-202.
30. Allen, D. L., Cleary, A. S., Speaker, K. J., Lindsay, S. F., Uyenishi, J., Reed, J. M., Madden, M. C. and Mehan, R. S. (2008) Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am. J. Physiol. Endocrinol. Metab. 294, E918-927.
31. Chen, T. L., Shen, W. J. and Kraemer, F. B. (2001) Human BMP-7/OP-1 induces the growth and differentiation of adipocytes and osteoblasts in bone marrow stromal cell cultures. J. Cell Biochem. 82, 187-199.
32. Neumann, K., Endres, M., Ringe, J., Flath, B., Manz, R., Haupl, T., Sittinger, M. and Kaps, C. (2007) BMP7 promotes adipogenic but not osteo-/chondrogenic differentiation of adult human bone marrow-derived stem cells in high-density micro-mass culture. J. Cell Biochem. 102, 626-637.
33. Richard, D., Carpentier, A. C., Dore, G., Ouellet, V. and Picard, F. (2010) Determinants of brown adipocyte development and thermogenesis. Int. J. Obes (Lond). 34 (SUPPL 2), S59-66.
34. Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E. L., Tseng, Y. H., Doria, A., Kolodny, G. M. and Kahn, C. R. (2009) Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509-1517.
35. Virtanen, K. A., Lidell, M. E., Orava, J., Heglind, M., Westergren, R., Niemi, T., Taittonen, M., Laine, J., Savisto, N. J., Enerback, S. and Nuutila, P. (2009) Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518-1525.
36. Saito, M., Okamatsu-Ogura, Y., Matsushita, M., Watanabe, K., Yoneshiro, T., Nio-Kobayashi, J., Iwanaga, T., Miyagawa, M., Kameya, T., Nakada, K., Kawai, Y. and Tsujisaki, M. (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526-1531.
37. Zingaretti, M. C., Crosta, F., Vitali, A., Guerrieri, M., Frontini, A., Cannon, B., Nedergaard, J. and Cinti, S. (2009) The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB. J. 23, 3113-3120.
38. Harris, M. I. (1998) Diabetes in America: epidemiology and scope of the problem. Diabetes Care. 21(SUPPL 3), C11-14.
39. Taylor, S. I. (1999) Deconstructing type 2 diabetes. Cell 97, 9-12.
40. Saltiel, A. R. (2001) New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104, 517-529.
41. Chen, J. W., Christiansen, J. S. and Lauritzen, T. (2003) Limitations to subcutaneous insulin administration in type 1 diabetes. Diabetes Obes. Metab. 5, 223-233.
42. Chen, W., Salojin, K. V., Mi, Q. S., Grattan, M., Meagher, T. C., Zucker, P. and Delovitch, T. L. (2004) Insulin-like growth factor (IGF)-I/IGF-binding protein-3 complex: therapeutic efficacy and mechanism of protection against type 1 diabetes. Endocrinology 145, 627-638.
43. Tobin, J. F. and Celeste, A. J. (2006) Bone morphogenetic proteins and growth differentiation factors as drug targets in cardiovascular and metabolic disease. Drug. Discov Today 11, 405-411.
44. Miller, A. F., Harvey, S. A., Thies, R. S. and Olson, M. S. (2000) Bone morphogenetic protein-9. An autocrine/paracrine cytokine in the liver. J. Biol. Chem. 275, 17937-17945.
45. Caperuto, L. C., Anhe, G. F., Cambiaghi, T. D., Akamine, E. H., do Carmo Buonfiglio, D., Cipolla-Neto, J., Curi, R. and Bordin, S. (2008) Modulation of bone morphogenetic protein-9 expression and processing by insulin, glucose, and glucocorticoids: possible candidate for hepatic insulin-sensitizing substance. Endocrinology 149, 6326-6335.
46. Lautt, W. W. (1999) The HISS story overview: a novel hepatic neurohumoral regulation of peripheral insulin sensitivity in health and diabetes. Can. J. Physiol. Pharmacol. 77, 553-562.
47. Bidart, M., Ricard, N., Levet, S., Samson, M., Mallet, C., David, L., Subileau, M., Tillet, E., Feige, J. J. and Bailly, S. (2011) BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell. Mol. Life. Sci. June 28. [Epub ahead of print].
48. Anhe, F. F., Lellis-Santos, C., Leite, A. R., Hirabara, S. M., Boschero, A. C., Curi, R., Anhe, G. F. and Bordin, S. (2010) Smad5 regulates Akt2 expression and insulin- induced glucose uptake in L6 myotubes. Mol. Cell. Endocrinol. 319, 30-38.
49. Song, J. J., Celeste, A. J., Kong, F. M., Jirtle, R. L., Rosen, V. and Thies, R. S. (1995) Bone morphogenetic protein-9 binds to liver cells and stimulates proliferation. Endocrinology 136, 4293-4297.
50. Chen, C., Grzegorzewski, K. J., Barash, S., Zhao, Q., Schneider, H., Wang, Q., Singh, M., Pukac, L., Bell, A. C., Duan, R., Coleman, T., Duttaroy, A., Cheng, S., Hirsch, J., Zhang, L., Lazard, Y., Fischer, C., Barber, M. C., Ma, Z. D., Zhang, Y. Q., Reavey, P., Zhong, L., Teng, B., Sanyal, I., Ruben, S. M., Blondel, O. and Birse, C. E. (2003) An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis. Nat. Biotechnol. 21, 294-301.
51. Wang, J., Greene, S. B. and Martin, J. F. (2011) BMP signaling in congenital heart disease: new developments and future directions. Birth. Defects. Res. A. Clin. Mol. Teratol. 91, 441-448.
52. Lowery, J. W. and de Caestecker, M. P. (2010) BMP signaling in vascular development and disease. Cytokine Growth Factor Rev. 21, 287-298.
53. Chen, N. X. and Moe, S. M. (2003) Arterial calcification in diabetes. Curr. Diab. Rep. 3, 28-32.
54. Liu, Y. and Shanahan, C. M. (2011) Signalling pathways and vascular calcification. Front. Biosci. 16, 1302-1314.
55. Rennenberg, R. J., Schurgers, L. J., Kroon, A. A. and Stehouwer, C. D. (2010) Arterial calcifications. J. Cell. Mol. Med. 14, 2203-2210.
56. Corriere, M. A., Rogers, C. M., Eliason, J. L., Faulk, J., Kume, T., Hogan, B. L. and Guzman, R. J. (2008) Endothelial Bmp4 is induced during arterial remodeling: effects on smooth muscle cell migration and proliferation. J. Surg. Res. 145, 142-149.
57. Bostrom, K., Watson, K. E., Horn, S., Wortham, C., Herman, I. M. and Demer, L. L. (1993) Bone morphogenetic protein expression in human atherosclerotic lesions. J. Clin. Invest. 91, 1800-1809.
58. Sorescu, G. P., Sykes, M., Weiss, D., Platt, M. O., Saha, A., Hwang, J., Boyd, N., Boo, Y. C., Vega, J. D., Taylor, W. R. and Jo, H. (2003) Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. J. Biol. Chem. 278, 31128-31135.
59. Cheng, S. L., Shao, J. S., Charlton-Kachigian, N., Loewy, A. P. and Towler, D. A. (2003) MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J. Biol. Chem. 278, 45969-45977.
60. Tobin, M. J. (2003) Chronic obstructive pulmonary disease, pollution, pulmonary vascular disease, transplantation, pleural disease, and lung cancer in AJRCCM 2002. Am. J. Respir. Crit. Care. Med. 167, 356-370.
61. Zebboudj, A. F., Imura, M. and Bostrom, K. (2002) Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. J. Biol. Chem. 277, 4388-4394.
62. Yao, Y., Zebboudj, A. F., Shao, E., Perez, M. and Bostrom, K. (2006) Regulation of bone morphogenetic protein-4 by matrix GLA protein in vascular endothelial cells involves activin-like kinase receptor 1. J. Biol. Chem. 281, 33921-33930.
63. Dhore, C. R., Cleutjens, J. P., Lutgens, E., Cleutjens, K. B., Geusens, P. P., Kitslaar, P. J., Tordoir, J. H., Spronk, H. M., Vermeer, C. and Daemen, M. J. (2001) Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 21, 1998-2003.
64. Luo, G., Ducy, P., McKee, M. D., Pinero, G. J., Loyer, E., Behringer, R. R. and Karsenty, G. (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386, 78-81.
65. Sweatt, A., Sane, D. C., Hutson, S. M. and Wallin, R. (2003) Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J. Thromb. Haemost. 1, 178-185.
66. Hur, D. J., Raymond, G. V., Kahler, S. G., Riegert-Johnson, D. L., Cohen, B. A. and Boyadjiev, S. A. (2005) A novel MGP mutation in a consanguineous family: review of the clinical and molecular characteristics of Keutel syndrome. Am. J. Med. Genet. A. 135, 36-40.
67. Hruska, K. A., Guo, G., Wozniak, M., Martin, D., Miller, S., Liapis, H., Loveday, K., Klahr, S., Sampath, T. K. and Morrissey, J. (2000) Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am. J. Physiol. Renal. Physiol. 279, F130-143.
68. Vukicevic, S., Basic, V., Rogic, D., Basic, N., Shih, M. S., Shepard, A., Jin, D., Dattatreyamurty, B., Jones, W., Dorai, H., Ryan, S., Griffiths, D., Maliakal, J., Jelic, M., Pastorcic, M., Stavljenic, A. and Sampath, T. K. (1998) Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J. Clin. Invest. 102, 202-214.
69. Simic, P. and Vukicevic, S. (2005) Bone morphogenetic proteins in development and homeostasis of kidney. Cytokine. Growth. Factor. Rev. 16, 299-308.
70. Zeisberg, M., Hanai, J., Sugimoto, H., Mammoto, T., Charytan, D., Strutz, F. and Kalluri, R. (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964-968.
71. Davies, M. R., Lund, R. J. and Hruska, K. A. (2003) BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J. Am. Soc. Nephrol. 14, 1559-1567.
72. Li, T., Surendran, K., Zawaideh, M. A., Mathew, S. and Hruska, K. A. (2004) Bone morphogenetic protein 7: a novel treatment for chronic renal and bone disease. Curr. Opin. Nephrol. Hypertens. 13, 417-422.
73. McAllister, K. A., Grogg, K. M., Johnson, D. W., Gallione, C. J., Baldwin, M. A., Jackson, C. E., Helmbold, E. A., Markel, D. S., McKinnon, W. C., Murrell, J. McCormick, M. K., Pericak-Vance, M. A., Heutink, P., Oostra, B. A., Haitjema, T., Westerman, C. J. J., Porteous, M. E., Guttmacher, A. E., Letarte, M. and Marchuk, D. A. (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat. Genet. 8, 345-351.
74. Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S. J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. and Marchuk, D. A. (1996) Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat. Genet. 13, 189-195.
75. Gallione, C. J., Richards, J. A., Letteboer, T. G., Rushlow, D., Prigoda, N. L., Leedom, T. P., Ganguly, A., Castells, A., Ploos van Amstel, J. K., Westermann, C. J., Pyeritz, R. E. and Marchuk, D. A. (2006) SMAD4 mutations found in unselected HHT patients. J. Med. Genet. 43, 793-797.
76. Sabba, C., Pasculli, G., Lenato, G. M., Suppressa, P., Lastella, P., Memeo, M., Dicuonzo, F. and Guant, G. (2007) Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J. Thromb. Haemost. 5, 1149-1157.
77. Oh, S. P., Seki, T., Goss, K. A., Imamura, T., Yi, Y., Donahoe, P. K., Li, L., Miyazono, K., ten Dijke, P., Kim, S. and Li, E. (2000) Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 97, 2626-2631.
78. Urness, L. D., Sorensen, L. K. and Li, D. Y. (2000) Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat. Genet. 26, 328-331.
79. Roman, B. L., Pham, V. N., Lawson, N. D., Kulik, M., Childs, S., Lekven, A. C., Garrity, D. M., Moon, R. T., Fishman, M. C., Lechleider, R. J. and Weinstein, B. M. (2002) Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129, 3009-3019.
80. Li, D. Y., Sorensen, L. K., Brooke, B. S., Urness, L. D., Davis, E. C., Taylor, D. G., Boak, B. B. and Wendel, D. P. (1999) Defective angiogenesis in mice lacking endoglin. Science 284, 1534-1537.
81. Liu, D., Wang, J., Kinzel, B., Mueller, M., Mao, X., Valdez, R., Liu, Y. and Li, E. (2007) Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity. Blood 110, 1502-1510.
82. Arthur, H. M., Ure, J., Smith, A. J., Renforth, G., Wilson, D. I., Torsney, E., Charlton, R., Parums, D. V., Jowett, T., Marchuk, D. A., Burn, J. and Diamond, A. G. (2000) Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev. Biol. 217, 42-53.
83. Srinivasan, S., Hanes, M. A., Dickens, T., Porteous, M. E., Oh, S. P., Hale, L. P. and Marchuk, D. A. (2003) A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum. Mol. Genet. 12, 473-482.
84. Park, S. O., Lee, Y. J., Seki, T., Hong, K. H., Fliess, N., Jiang, Z., Park, A., Wu, X., Kaartinen, V., Roman, B. L. and Oh, S. P. (2008) ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 111, 633-642.
85. Bourdeau, A., Faughnan, M. E. and Letarte, M. (2000) Endoglin-deficient mice, a unique model to study hereditary hemorrhagic telangiectasia. Trends. Cardiovasc. Med. 10, 279-285.
86. Bourdeau, A., Cymerman, U., Paquet, M. E., Meschino, W., McKinnon, W. C., Guttmacher, A. E., Becker, L. and Letarte, M. (2000) Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am. J. Pathol. 156, 911-923.
87. Mitchell, A., Adams, L. A., MacQuillan, G., Tibballs, J., vanden Driesen, R. and Delriviere, L. (2008) Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver. Transpl. 14, 210-213.
88. Cruikshank, R. P. and Chern, B. W. (2011) Bevacizumab and hereditary haemorrhagic telangiectasia. Med. J. Aust. 194, 324-325.
89. Machado, R. D., Aldred, M. A., James, V., Harrison, R. E., Patel, B., Schwalbe, E. C., Gruenig, E., Janssen, B., Koehler, R., Seeger, W., Eickelberg, O., Olschewski, H., Elliott, C. G., Glissmeyer, E., Carlquist, J., Kim, M., Torbicki, A., Fijalkowska, A., Szewczyk, G., Parma, J., Abramowicz, M. J., Galie, N., Morisaki, H., Kyotani, S., Nakanishi, N., Morisaki, T., Humbert, M., Simonneau, G., Sitbon, O., Soubrier, F., Coulet, F., Morrell, N. W. and Trembath, R. C. (2006) Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum. Mutat. 27, 121-132.
90. Machado, R. D., Eickelberg, O., Elliott, C. G., Geraci, M. W., Hanaoka, M., Loyd, J. E., Newman, J. H., Phillips, J. A., 3rd, Soubrier, F., Trembath, R. C. and Chung, W. K. (2009) Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S32-42.
91. Lane, K. B., Machado, R. D., Pauciulo, M. W., Thomson, J. R., Phillips, J. A., 3rd, Loyd, J. E., Nichols, W. C. and Trembath, R. C. (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat. Genet. 26, 81-84.
92. Thomson, J. R., Machado, R. D., Pauciulo, M. W., Morgan, N. V., Humbert, M., Elliott, G. C., Ward, K., Yacoub, M., Mikhail, G., Rogers, P., Newman, J., Wheeler, L., Higenbottam, T., Gibbs, J. S., Egan, J., Crozier, A., Peacock, A., Allcock, R., Corris, P., Loyd, J. E., Trembath, R. C. and Nichols, W. C. (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J. Med. Genet. 37, 741-745.
93. Simonneau, G., Galie, N., Rubin, L. J., Langleben, D., Seeger, W., Domenighetti, G., Gibbs, S., Lebrec, D., Speich, R., Beghetti, M., Rich, S. and Fishman, A. (2004) Clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 43, S5-12.
94. Du, L., Sullivan, C. C., Chu, D., Cho, A. J., Kido, M., Wolf, P. L., Yuan, J. X., Deutsch, R., Jamieson, S. W. and Thistlethwaite, P. A. (2003) Signaling molecules in nonfamilial pulmonary hypertension. N. Engl. J. Med. 348, 500-509.
95. Atkinson, C., Stewart, S., Upton, P. D., Machado, R., Thomson, J. R., Trembath, R. C. and Morrell, N. W. (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105, 1672-1678.
96. Humbert, M., Deng, Z., Simonneau, G., Barst, R. J., Sitbon, O., Wolf, M., Cuervo, N., Moore, K. J., Hodge, S. E., Knowles, J. A. and Morse, J. H. (2002) BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur. Respir. J. 20, 518-523.
97. Lowery, J. W., Frump, A. L., Anderson, L., DiCarlo, G. E., Jones, M. T. and de Caestecker, M. P. (2010) ID family protein expression and regulation in hypoxic pulmonary hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R1463-1477.
98. Foletta, V. C., Lim, M. A., Soosairajah, J., Kelly, A. P., Stanley, E. G., Shannon, M., He, W., Das, S., Massague, J. and Bernard, O. (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J. Cell. Biol. 162, 1089-1098.
99. Frank, D. B., Lowery, J., Anderson, L., Brink, M., Reese, J. and de Caestecker, M. (2008) Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am. J. Physiol. Lung. Cell. Mol. Physiol. 294, L98-109.
100. Hong, K. H., Lee, Y. J., Lee, E., Park, S. O., Han, C., Beppu, H., Li, E., Raizada, M. K., Bloch, K. D. and Oh, S. P. (2008) Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation. 118, 722-730.
101. Song, Y., Coleman, L., Shi, J., Beppu, H., Sato, K., Walsh, K., Loscalzo, J. and Zhang, Y. Y. (2008) Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am. J. Physiol. Heart Circ. Physiol. 295, H677-690.
102. Song, Y., Jones, J. E., Beppu, H., Keaney, J. F., Jr., Loscalzo, J. and Zhang, Y. Y. (2005) Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 112, 553-562.
103. West, J. (2010) Cross talk between Smad, MAPK, and actin in the etiology of pulmonary arterial hypertension. Adv. Exp. Med. Biol. 661, 265-278.
104. Reynolds, P. N. (2011) Gene therapy for pulmonary hypertension: prospects and challenges. Expert. Opin. Biol. Ther. 11, 133-143.
105. Reynolds, P. N. (2011) Viruses in pharmaceutical research: pulmonary vascular disease. Mol. Pharm. 8, 56-64.
106. Yuan, J. X. and Rubin, L. J. (2005) Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. Circulation 111, 534-538.
107. Baliga, R. S., MacAllister, R. J. and Hobbs, A. J. (2011) New perspectives for the treatment of pulmonary hypertension. Br. J. Pharmacol. 163, 125-140.
108. Pardali, E. and ten Dijke, P. (2009) Transforming growth factor-beta signaling and tumor angiogenesis. Front Biosci. 14, 4848-4861.
109. Massague, J. (2008) TGFbeta in Cancer. Cell 134, 215-230.
110. Singh, A. and Morris, R. J. (2010) The Yin and Yang of bone morphogenetic proteins in cancer. Cytokine. Growth. Factor. Rev. 21, 299-313.
111. Wharton, K. and Derynck, R. (2009) TGFbeta family signaling: novel insights in development and disease. Development 136, 3691-3697.
112. Walsh, D. W., Godson, C., Brazil, D. P. and Martin, F. (2010) Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends. Cell Biol. 20, 244-256.
113. Kleeff, J., Maruyama, H., Ishiwata, T., Sawhney, H., Friess, H., Buchler, M. W. and Korc, M. (1999) Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. Gastroenterology 116, 1202-1216.
114. Herrera, B., van Dinther, M., Ten Dijke, P. and Inman, G. J. (2009) Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/ Smad4 to promote ovarian cancer cell proliferation. Cancer Res. 69, 9254-9262.
115. Alarmo, E. L., Parssinen, J., Ketolainen, J. M., Savinainen, K., Karhu, R. and Kallioniemi, A. (2009) BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett. 275, 35-43.
116. Arnold, S. F., Tims, E. and McGrath, B. E. (1999) Identification of bone morphogenetic proteins and their receptors in human breast cancer cell lines: importance of BMP2. Cytokine. 11, 1031-1037.
117. Ro, T. B., Holt, R. U., Brenne, A. T., Hjorth-Hansen, H., Waage, A., Hjertner, O., Sundan, A. and Borset, M. (2004) Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells. Oncogene 23, 3024-3032.
118. Piccirillo, S. G., Reynolds, B. A., Zanetti, N., Lamorte, G., Binda, E., Broggi, G., Brem, H., Olivi, A., Dimeco, F. and Vescovi, A. L. (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761-765.
119. Du, J., Yang, S., Wang, Z., Zhai, C., Yuan, W., Lei, R., Zhang, J. and Zhu, T. (2008) Bone morphogenetic protein 6 inhibit stress-induced breast cancer cells apoptosis via both Smad and p38 pathways. J. Cell. Biochem. 103, 1584-1597.
120. Johnsen, I. K., Kappler, R., Auernhammer, C. J. and Beuschlein, F. (2009) Bone morphogenetic proteins 2 and 5 are down-regulated in adrenocortical carcinoma and modulate adrenal cell proliferation and steroidogenesis. Cancer Res. 69, 5784-5792.
121. Quan, G. M. and Choong, P. F. (2006) Anti-angiogenic therapy for osteosarcoma. Cancer Metastasis Rev. 25, 707-713.
122. Hanahan, D. and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674.
123. Bergers, G. and Benjamin, L. E. (2003) Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3, 401-410.
124. Carmeliet, P. (2005) Angiogenesis in life, disease and medicine. Nature 438, 932-936.
125. Carmeliet, P. (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology (Williston Park). 69(Suppl 3), 4-10.
126. David, L., Feige, J. J. and Bailly, S. (2009) Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine. Growth. Factor Rev. 20, 203-212.
127. Langenfeld, E. M. and Langenfeld, J. (2004) Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol. Cancer Res. 2, 141-149.
128. Valdimarsdottir, G., Goumans, M. J., Rosendahl, A., Brugman, M., Itoh, S., Lebrin, F., Sideras, P. and ten Dijke, P. (2002) Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation 106, 2263-2270.
129. Raida, M., Clement, J. H., Leek, R. D., Ameri, K., Bicknell, R., Niederwieser, D. and Harris, A. L. (2005) Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis. J. Cancer Res. Clin. Oncol. 131, 741-750.
130. Peng, H., Usas, A., Olshanski, A., Ho, A. M., Gearhart, B., Cooper, G. M. and Huard, J. (2005) VEGF improves, whereas sFlt1 inhibits, BMP2-induced bone formation and bone healing through modulation of angiogenesis. J. Bone Miner. Res. 20, 2017-2027.
131. Rothhammer, T., Bataille, F., Spruss, T., Eissner, G. and Bosserhoff, A. K. (2007) Functional implication of BMP4 expression on angiogenesis in malignant melanoma. Oncogene 26, 4158-4170.
132. Smadja, D. M., Bieche, I., Silvestre, J. S., Germain, S., Cornet, A., Laurendeau, I., Duong-Van-Huyen, J. P., Emmerich, J., Vidaud, M., Aiach, M. and Gaussem, P. (2008) Bone morphogenetic proteins 2 and 4 are selectively expressed by late outgrowth endothelial progenitor cells and promote neoangiogenesis. Arterioscler. Thromb. Vasc. Biol. 28, 2137-2143.
133. Bieniasz, M., Oszajca, K., Eusebio, M., Kordiak, J., Bartkowiak, J. and Szemraj, J. (2009) The positive correlation between gene expression of the two angiogenic factors: VEGF and BMP-2 in lung cancer patients. Lung Cancer 66, 319-326.
134. Moreno-Miralles, I., Schisler, J. C. and Patterson, C. (2009) New insights into bone morphogenetic protein signaling: focus on angiogenesis. Curr. Opin. Hematol. 16, 195-201.
135. Nimmagadda, S., Geetha Loganathan, P., Huang, R., Scaal, M., Schmidt, C. and Christ, B. (2005) BMP4 and noggin control embryonic blood vessel formation by antagonistic regulation of VEGFR-2 (Quek1) expression. Dev. Biol. 280, 100-110.
136. Scharpfenecker, M., van Dinther, M., Liu, Z., van Bezooijen, R. L., Zhao, Q., Pukac, L., Lowik, C. W. and ten Dijke, P. (2007) BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGFstimulated angiogenesis. J. Cell. Sci. 120, 964-972.
137. David, L., Mallet, C., Keramidas, M., Lamande, N., Gasc, J. M., Dupuis-Girod, S., Plauchu, H., Feige, J. J. and Bailly, S. (2008) Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ. Res. 102, 914-922.
138. Liu, Z., Kobayashi, K., van Dinther, M., van Heiningen, S. H., Valdimarsdottir, G., van Laar, T., Scharpfenecker, M., Lowik, C. W., Goumans, M. J., Ten Dijke, P. and Pardali, E. (2009) VEGF and inhibitors of TGFbeta type-I receptor kinase synergistically promote blood-vessel formation by inducing alpha5-integrin expression. J. Cell. Sci. 122, 3294-3302.
139. Mitchell, D., Pobre, E. G., Mulivor, A. W., Grinberg, A. V., Castonguay, R., Monnell, T. E., Solban, N., Ucran, J. A., Pearsall, R. S., Underwood, K. W., Seehra, J. and Kumar, R. (2010) ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth. Mol. Cancer. Ther. 9, 379-388.
140. Mitchell, D. C. and Bryan, B. A. (2010) Anti-angiogenic therapy: adapting strategies to overcome resistant tumors. J. Cell Biochem. 111, 543-553.
141. Hay, E. D. and Zuk, A. (1995) Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am. J. Kidney. Dis. 26, 678-690.
142. Klymkowsky, M. W. and Savagner, P. (2009) Epithelialmesenchymal transition: a cancer researcher's conceptual friend and foe. Am. J. Pathol. 174, 1588-1593.
143. Polyak, K. and Weinberg, R. A. (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer. 9, 265-273.
144. Thiery, J. P., Acloque, H., Huang, R. Y. and Nieto, M. A. (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890.
145. Yilmaz, M. and Christofori, G. (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer. Metastasis. Rev. 28, 15-33.
146. Barrallo-Gimeno, A. and Nieto, M. A. (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132, 3151-3161.
147. Sethi, N. and Kang, Y. (2011) Dysregulation of developmental pathways in bone metastasis. Bone 48, 16-22.
148. Ma, L., Lu, M. F., Schwartz, R. J. and Martin, J. F. (2005) Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development 132, 5601-5611.
149. Theriault, B. L., Shepherd, T. G., Mujoomdar, M. L. and Nachtigal, M. W. (2007) BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis. 28, 1153-1162.
150. Feeley, B. T., Krenek, L., Liu, N., Hsu, W. K., Gamradt, S. C., Schwarz, E. M., Huard, J. and Lieberman, J. R. (2006) Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone 38, 154-166.
151. Clement, J. H., Raida, M., Sanger, J., Bicknell, R., Liu, J., Naumann, A., Geyer, A., Waldau, A., Hortschansky, P., Schmidt, A., Hoffken, K., Wolft, S. and Harris, A. L. (2005) Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int. J. Oncol. 27, 401-407.
152. Katsuno, Y., Hanyu, A., Kanda, H., Ishikawa, Y., Akiyama, F., Iwase, T., Ogata, E., Ehata, S., Miyazono, K. and Imamura, T. (2008) Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27, 6322-6333.
153. Moreau, J. E., Anderson, K., Mauney, J. R., Nguyen, T., Kaplan, D. L. and Rosenblatt, M. (2007) Tissue-engineered bone serves as a target for metastasis of human breast cancer in a mouse model. Cancer Res. 67, 10304-10308.
154. Deng, H., Ravikumar, T. S. and Yang, W. L. (2007) Bone morphogenetic protein-4 inhibits heat-induced apoptosis by modulating MAPK pathways in human colon cancer HCT116 cells. Cancer Lett. 256, 207-217.
155. Kang, M. H., Kim, J. S., Seo, J. E., Oh, S. C. and Yoo, Y. A. (2010) BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Exp. Cell. Res. 316, 24-37.
156. Orr, F. W., Sanchez-Sweatman, O. H., Kostenuik, P. and Singh, G. (1995) Tumor-bone interactions in skeletal metastasis. Clin. Orthop. Relat. Res. 312, 19-33.
157. Mundy, G. R. (1997) Mechanisms of bone metastasis. Cancer 80, 1546-1556.
158. Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J. and Thun, M. J. (2009) Cancer statistics, 2009. CA. Cancer. J. Clin. 59, 225-249.
159. Coleman, R. E. (1997) Skeletal complications of malignancy. Cancer 80, 1588-1594.
160. Galasko, C. S. (1986) Skeletal metastases. Clin. Orthop. Relat. Res. 210, 18-30.
161. Bussard, K. M., Gay, C. V. and Mastro, A. M. (2008) The bone microenvironment in metastasis; what is special about bone? Cancer Metastasis. Rev. 27, 41-55.
162. Davies, S. R., Watkins, G., Douglas-Jones, A., Mansel, R. E. and Jiang, W. G. (2008) Bone morphogenetic proteins 1 to 7 in human breast cancer, expression pattern and clinical/prognostic relevance. J. Exp. Ther. Oncol. 7, 327-338.
163. McMurtry, I. F. (2002) Introduction: pre- and postnatal lung development, maturation, and plasticity. Am. J. Physiol. Lung. Cell. Mol. Physiol. 282, L341-344.
164. Mundy, G. R. (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2, 584-593.
165. Ye, L., Mason, M. D. and Jiang, W. G. (2011) Bone morphogenetic protein and bone metastasis, implication and therapeutic potential. Front Biosci. 16, 865-897.
166. Roodman, G. D. (2004) Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655-1664.
167. Lu, X. and Kang, Y. (2010) Epidermal growth factor signalling and bone metastasis. Br. J. Cancer 102, 457-461.
168. Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Cordon-Cardo, C., Guise, T. A. and Massague, J. (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 3, 537-549.
169. Mastro, A. M., Gay, C. V. and Welch, D. R. (2003) The skeleton as a unique environment for breast cancer cells. Clin. Exp. Metastasis. 20, 275-284.
170. Schneider, A., Kalikin, L. M., Mattos, A. C., Keller, E. T., Allen, M. J., Pienta, K. J. and McCauley, L. K. (2005) Bone turnover mediates preferential localization of prostate cancer in the skeleton. Endocrinology 146, 1727-1736.
171. Senta, H., Park, H., Bergeron, E., Drevelle, O., Fong, D., Leblanc, E., Cabana, F., Roux, S., Grenier, G. and Faucheux, N. (2009) Cell responses to bone morphogenetic proteins and peptides derived from them: biomedical applications and limitations. Cytokine. Growth. Factor. Rev. 20, 213-222.
172. Graham, T. R., Agrawal, K. C. and Abdel-Mageed, A. B. (2010) Independent and cooperative roles of tumor necrosis factor-alpha, nuclear factor-kappaB, and bone morphogenetic protein-2 in regulation of metastasis and osteomimicry of prostate cancer cells and differentiation and mineralization of MC3T3-E1 osteoblast-like cells. Cancer Sci. 101, 103-111.
173. Rucci, N. and Teti, A. (2010) Osteomimicry: how tumor cells try to deceive the bone. Front. Biosci (Elite Ed). 2, 907-915.
174. Bailey, J. M., Singh, P. K. and Hollingsworth, M. A. (2007) Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. J. Cell. Biochem. 102, 829-839.
175. Kalluri, R. and Zeisberg, M. (2006) Fibroblasts in cancer. Nat. Rev. Cancer 6, 392-401.
176. Cooper, C. R., Chay, C. H., Gendernalik, J. D., Lee, H. L., Bhatia, J., Taichman, R. S., McCauley, L. K., Keller, E. T. and Pienta, K. J. (2003) Stromal factors involved in prostate carcinoma metastasis to bone. Cancer 97, 739-747.
177. Spradling, A., Drummond-Barbosa, D. and Kai, T. (2001) Stem cells find their niche. Nature 414, 98-104.
178. Blanco Calvo, M., Bolos Fernandez, V., Medina Villaamil, V., Aparicio Gallego, G., Diaz Prado, S. and Grande Pulido, E. (2009) Biology of BMP signalling and cancer. Clin. Transl. Oncol. 11, 126-137.
179. Qiao, B., Johnson, N. W., Chen, X., Li, R., Tao, Q. and Gao, J. (2011) Disclosure of a stem cell phenotype in an oral squamous cell carcinoma cell line induced by BMP-4 via an epithelial-mesenchymal transition. Oncol. Rep. 26, 455-461.
180. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., Brooks, M., Reinhard, F., Zhang, C. C., Shipitsin, M., Campbell, L. L., Polyak, K., Brisken, C., Yang, J. and Weinberg, R. A. (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715.
181. Carlson, M. E. and Conboy, I. M. (2007) Regulating the Notch pathway in embryonic, adult and old stem cells. Curr. Opin. Pharmacol. 7, 303-309.
182. Zhang, M. and Rosen, J. M. (2006) Stem cells in the etiology and treatment of cancer. Curr. Opin. Genet. Dev. 16, 60-64.
183. Katoh, M. (2011) Network of WNT and other regulatory signaling cascades in pluripotent stem cells and cancer stem cells. Curr. Pharm. Biotechnol. 12, 160-170.
184. Katoh, M. (2007) Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem. Cell. Rev. 3, 30-38.
185. Lombardo, Y., Scopelliti, A., Cammareri, P., Todaro, M., Iovino, F., Ricci-Vitiani, L., Gulotta, G., Dieli, F., de Maria, R. and Stassi, G. (2011) Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140, 297-309.
186. Yauch, R. L., Gould, S. E., Scales, S. J., Tang, T., Tian, H., Ahn, C. P., Marshall, D., Fu, L., Januario, T., Kallop, D., Nannini-Pepe, M., Kotkow, K., Marsters, J. C., Rubin, L. L. and de Sauvage, F. J. (2008) A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406-410.
187. Von Hoff, D. D., LoRusso, P. M., Rudin, C. M., Reddy, J. C., Yauch, R. L., Tibes, R., Weiss, G. J., Borad, M. J., Hann, C. L., Brahmer, J. R., Mackey, H. M., Lum, B. L., Darbonne, W. C., Marsters, J. C. Jr., de Sauvage, F. J. and Low, J. A. (2009) Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164-1172.
188. Yu, P. B., Hong, C. C., Sachidanandan, C., Babitt, J. L., Deng, D. Y., Hoyng, S. A., Lin, H. Y., Bloch, K. D. and Peterson, R. T. (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 4, 33-41.
189. Jiang, W. G., Martin, T. A., Lewis-Russell, J. M., Douglas-Jones, A., Ye, L. and Mansel, R. E. (2008) Eplin-alpha expression in human breast cancer, the impact on cellular migration and clinical outcome. Mol. Cancer 7, 71.
190. Ye, L., Kynaston, H. and Jiang, W. G. (2008) Bone morphogenetic protein-9 induces apoptosis in prostate cancer cells, the role of prostate apoptosis response-4. Mol. Cancer Res. 6, 1594-1606.
191. Ong, K. L., Villarraga, M. L., Lau, E., Carreon, L. Y., Kurtz, S. M. and Glassman, S. D. (2010) Off-label use of bone morphogenetic proteins in the United States using administrative data. Spine (Phila Pa 1976). 35, 1794-1800.
192. Thawani, J. P., Wang, A. C., Than, K. D., Lin, C. Y., La Marca, F. and Park, P. (2010) Bone morphogenetic proteins and cancer: review of the literature. Neurosurgery 66, 233-246.
193. Poynton, A. R. and Lane, J. M. (2002) Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine (Phila Pa 1976). 27, S40-48.
194. Sundaresan, N., Boriani, S., Rothman, A. and Holtzman, R. (2004) Tumors of the osseous spine. J. Neurooncol. 69, 273-290.
195. Benglis, D., Wang, M. Y. and Levi, A. D. (2008) A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery 62, ONS-423-431.
196. Nakashima, M. and Reddi, A. H. (2003) The application of bone morphogenetic proteins to dental tissue engineering. Nat. Biotechnol. 21, 1025-1032.
197. Seeherman, H. and Wozney, J. M. (2005) Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine. Growth. Factor. Rev. 16, 329-345.
198. Bessa, P. C., Casal, M. and Reis, R. L. (2008) Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts). J. Tissue. Eng. Regen. Med. 2, 1-13.
199. Wozney, J. M., Rosen, V., Celeste, A. J., Mitsock, L. M., Whitters, M. J., Kriz, R. W., Hewick, R. M. and Wang, E. A. (1988) Novel regulators of bone formation: molecular clones and activities. Science 242, 1528-1534.
200. Schmidmaier, G., Schwabe, P., Strobel, C. and Wildemann, B. (2008) Carrier systems and application of growth factors in orthopaedics. Injury 39(Suppl 2), S37-43.
201. Gottfried, O. N. and Dailey, A. T. (2008) Mesenchymal stem cell and gene therapies for spinal fusion. Neurosurgery 63, 380-391.
202. Alaoui-Ismaili, M. H. and Falb, D. (2009) Design of second generation therapeutic recombinant bone morphogenetic proteins. Cytokine. Growth. Factor. Rev. 20, 501-507.
203. Allendorph, G. P., Read, J. D., Kawakami, Y., Kelber, J. A., Isaacs, M. J. and Choe, S. (2011) Designer TGF-beta superfamily ligands with diversified functionality. PLoS One., In press.
204. Saito, A., Suzuki, Y., Ogata, S., Ohtsuki, C. and Tanihara, M. (2003) Activation of osteo-progenitor cells by a novel synthetic peptide derived from the bone morphogenetic protein-2 knuckle epitope. Biochim. Biophys. Acta. 1651, 60-67.
205. Bergeron, E., Marquis, M. E., Chretien, I. and Faucheux, N. (2007) Differentiation of preosteoblasts using a delivery system with BMPs and bioactive glass microspheres. J. Mater. Sci. Mater. Med. 18, 255-263.
206. Geiger, M., Li, R. H. and Friess, W. (2003) Collagen sponges for bone regeneration with rhBMP-2. Adv. Drug. Deliv. Rev. 55, 1613-1629.
207. Uludag, H., Friess, W., Williams, D., Porter, T., Timony, G., D'Augusta, D., Blake, C., Palmer, R., Biron, B. and Wozney, J. (1999) rhBMP-collagen sponges as osteoinductive devices: effects of in vitro sponge characteristics and protein pI on in vivo rhBMP pharmacokinetics. Ann. N. Y. Acad. Sci. 875, 369-378.
208. Kempen, D. H., Lu, L., Hefferan, T. E., Creemers, L. B., Maran, A., Classic, K. L., Dhert, W. J. and Yaszemski, M. J. (2008) Retention of in vitro and in vivo BMP-2 bioactivities in sustained delivery vehicles for bone tissue engineering. Biomaterials. 29, 3245-3252.
209. Zambaux, M. F., Bonneaux, F., Gref, R., Maincent, P., Dellacherie, E., Alonso, M. J., Labrude, P. and Vigneron, C. (1998) Influence of experimental parameters on the characteristics of poly (lactic acid) nanoparticles prepared by a double emulsion method. J. Control. Release. 50, 31-40.
210. Franceschi, R. T. (2005) Biological approaches to bone regeneration by gene therapy. J. Dent. Res. 84, 1093-1103.
211. Li, H. Y., Neill, H., Innocent, R., Seville, P., Williamson, I. and Birchall, J. C. (2003) Enhanced dispersibility and deposition of spray-dried powders for pulmonary gene therapy. J. Drug. Target. 11, 425-432.