ABB  Vol.4 No.10 C , October 2013
From skeletal to non skeletal: The intriguing roles of BMP-9: A literature review
ABSTRACT

In the well-known superfamily of transforming growth factors beta (TGF-b), bone morphogenetic proteins (BMPs) are one of the most compelling cytokines for their major role in regulation of cell growth and differentiation in both embryonic and adult tissues. This subfamily was first described for its ability of potentiating bone formation, but nowadays, the power of BMPs is well beyond the bone healing scope. Some of the BMPs have been well studied and described in the literature, but the BMP9 is still worthy of attention. It has been shown by many authors that it is the most potent osteogenic BMP. Moreover, it has been described as one of the rare circulating BMPs. In this paper, we will review the recent literature on BMP9 and the different avenues for future research in that field. Our primary scope is to review its relation to bone formation and to elaborate on the available literature on other systems.


Cite this paper
Leblanc, E. , Drouin, G. , Grenier, G. , Faucheux, N. and Hamdy, R. (2013) From skeletal to non skeletal: The intriguing roles of BMP-9: A literature review. Advances in Bioscience and Biotechnology, 4, 31-46. doi: 10.4236/abb.2013.410A4004.
References
[1]   [1] Urist, M.R. (1965) Bone: Formation by autoinduction. Science, 150, 893-899.
http://dx.doi.org/10.1126/science.150.3698.893

[2]   NCBI. GDF2 growth differentiation 2 [Homo sapiens (human)], Gene, NCBI.
http://www.ncbi.nlm.nih.gov/gene/2658

[3]   Kishigami, S. and Mishina, Y. (2005) BMP signaling and early embryonic patterning. Cytokine Growth Factor Reviews, 16, 265-278.

[4]   Israel, D.I., Nove, J., Kerns, K.M., Kaufman, R.J., Rosen, V., Cox, K.A. and Wozney, J.M. (1996) Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth Factors, 13, 291-300.
http://dx.doi.org/10.3109/08977199609003229

[5]   Aono, A., Hazama, M., Notoya, K., Taketomi, S., Yamasaki, H., Tsukuda, R., Sasaki, S. and Fujisawa, Y. (1995) Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer. Biochemical and Biophysical Research Communications, 210, 670-677.
http://dx.doi.org/10.1006/bbrc.1995.1712

[6]   Miyazono, K., Maeda, S. and Imamura, T. (2005) BMP receptor signaling: Transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Reviews, 16, 251-263.
http://dx.doi.org/10.1016/j.cytogfr.2005.01.009

[7]   Mazerbourg, S. and Hsueh, A.J. (2006) Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands. Human Reproduction Update, 12, 373-383. http://dx.doi.org/10.1093/humupd/dml014

[8]   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). Journal of Tissue Engineering and Regenerative Medicine, 2, 1-13. http://dx.doi.org/10.1002/term.63

[9]   Wotton, K.R., Alcaine Colet, A., Jaeger, J. and JimenezGuri, E. (2013) Evolution and expression of BMP genes in flies. Development Genes and Evolution, 223, 335-340.
http://dx.doi.org/10.1007/s00427-013-0445-9

[10]   Kitisin, K., Saha, T., Blake, T., Golestaneh, N., Deng, M., Kim, C., Tang, Y., Shetty, K., Mishra, B. and Mishra, L. (2007) Tgf-Beta signaling in development. Science STKE, 399, cm1. http://dx.doi.org/10.1126/stke.3992007cm1

[11]   Chen, D., Zhao, M. and Mundy, G.R. (2004) Bone morphogenetic proteins. Growth Factors, 22, 233-241.
http://dx.doi.org/10.1080/08977190412331279890

[12]   Bergeron, E., Senta, H., Mailloux, A., Park, H., Lord, E. and Faucheux, N. (2009) Murine preosteoblast differentiation induced by a peptide derived from bone morphogenetic proteins-9. Tissue Eng Part A, 15, 3341-3349.
http://dx.doi.org/10.1089/ten.tea.2009.0189

[13]   Kang, Q., Song, W.X., Luo, Q., Tang, N., Luo, J., Luo, X., et al. (2009) A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells and Development, 18, 545-559.
http://dx.doi.org/10.1089/scd.2008.0130

[14]   Kang, Q., Sun, M.H., Cheng, H., Peng, Y., Montag, A.G., Deyrup, A.T., et al., (2004) Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Therapy, 11, 1312-1320.
http://dx.doi.org/10.1038/sj.gt.3302298

[15]   Cheng, H., Jiang, W., Phillips, F.M., Haydon, R.C., Peng, Y., Zhou, L., et al. (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). The Journal of Bone & Joint Surgery, 85-A, 1544-1552.

[16]   Peng, Y., Kang, Q., Cheng, H., Li, X., Sun, M.H., Jiang, W., et al. (2003) Transcriptional characterization of bone morphogenetic proteins (BMPs)-mediated osteogenic signaling. Journal of Cellular Biochemistry, 90, 1149-1165.
http://dx.doi.org/10.1002/jcb.10744

[17]   Li, J.Z., Hankins, G.R., Kao, C., Li, H., Kammauff, J. and Helm, G.A. (2003) Osteogenesis in rats induced by a novel recombinant helper-dependent bone morphogenetic protein-9 (BMP-9) adenovirus. The Journal of Gene Medicine, 5, 748-756.
http://dx.doi.org/10.1002/jgm.412

[18]   Wang, Y., Hong, S., Li, M., Zhang, J., Bi, Y., He, Y., et al. (2013) Noggin resistance contributes to the potent osteogenic capability of BMP9 in mesenchymal stem cells. Journal of Orthopaedic Research.
http://dx.doi.org/10.1002/jor.22427

[19]   van der Horst, G., van Bezooijen, R.L., Deckers, M.M., Hoogendam, J., Visser, A., Lowik, C.W. and Karperien, M. (2002) Differentiation of murine preosteoblastic KS483 cells depends on autocrine bone morphogenetic protein signaling during all phases of osteoblast formation. Bone, 31, 661-669.
http://dx.doi.org/10.1016/S8756-3282(02)00903-1

[20]   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. The Journal of Biological Chemistry, 275, 17937-17945.
http://dx.doi.org/10.1074/jbc.275.24.17937

[21]   Bidart, M., Ricard, N., Levet, S., Samson, M., Mallet, C., David, L., Subileau, M., Tillet, E., Feige, J.J. and Bailly, S. (2012) BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cellular and Molecular Life Sciences, 69, 313-324. http://dx.doi.org/10.1007/s00018-011-0751-1

[22]   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. Circulation Research, 102, 914-922.
http://dx.doi.org/10.1161/CIRCRESAHA.107.165530

[23]   Brown, M.A., Zhao, Q., Baker, K.A., Naik, C., Chen, C., Pukac, L., et al. (2005) Crystal structure of BMP-9 and functional interactions with pro-region and receptors. The Journal of Biological Chemistry, 280, 25111-25118.
http://dx.doi.org/10.1074/jbc.M503328200

[24]   David, L., Mallet, C., Mazerbourg, S., Feige, J.J. and Bailly, S. (2007) Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood, 109, 1953-1961. http://dx.doi.org/10.1182/blood-2006-07-034124

[25]   Cunha, S.I. and Pietras, K. (2011) ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood, 117, 6999-7006.
http://dx.doi.org/10.1182/blood-2011-01-330142

[26]   Attisano, L., Carcamo, J., Ventura, F., Weis, F.M., Massague, J. and Wrana, J.L. (1993) Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell, 75, 671-680.
http://dx.doi.org/10.1016/0092-8674(93)90488-C

[27]   Lamplot, J.D., Qin, J., Nan, G., Wang, J., Liu, X., Yin, L., et al. (2013) BMP9 signaling in stem cell differentiation and osteogenesis. American Journal of Stem Cells, 2, 1-21.

[28]   Bandyopadhyay, A., Yadav, P.S. and Prashar, P. (2013) BMP signaling in development and diseases: A pharmacological perspective. Biochemical Pharmacology, 85, 857-864. http://dx.doi.org/10.1016/j.bcp.2013.01.004

[29]   Kim, S.I., Kwak, J.H., Zachariah, M., He, Y., Wang, L. and Choi, M.E. (2007) TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. AJP: Renal Physiology, 292, F1471-F1478.

[30]   Luo, J., Tang, M., Huang, J., He, B.C., Gao, J.L., Chen, L., et al. (2010) TGF{beta}/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells. The Journal of Biological Chemistry.

[31]   Townson, S.A., Martinez-Hackert, E., Greppi, C., Lowden, P., Sako, D., Liu, J., et al. (2012) Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. The Journal of Biological Chemistry, 287, 27313-27325.
http://dx.doi.org/10.1074/jbc.M112.377960

[32]   Luther, G., Wagner, E.R., Zhu, G., Kang, Q., Luo, Q., Lamplot, J., et al. (2011) BMP-9 induced osteogenic differentiation of mesenchymal stem cells: Molecular mechanism and therapeutic potential. Current Gene Therapy, 11, 229-240.
http://dx.doi.org/10.2174/156652311795684777

[33]   Huang, E., Zhu, G., Jiang, W., Yang, K., Gao, Y., Luo, Q., et al. (2012) Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/ IGF1 pathway in murine multilineage cells. Journal of Bone and Mineral Research, 27, 1566-1575.
http://dx.doi.org/10.1002/jbmr.1622

[34]   Liu, X., Qin, J., Luo, Q., Bi, Y., Zhu, G., Jiang, W., et al. (2013) Cross-talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells. Journal of Cellular and Molecular Medicine. http://dx.doi.org/10.1111/jcmm.12097

[35]   Suttapreyasri, S., Koontongkaew, S., Phongdara, A. and Leggat, U. (2006) Expression of bone morphogenetic proteins in normal human intramembranous and endochondral bones. International Journal of Oral and Maxillofacial Surgery, 35, 444-452.
http://dx.doi.org/10.1016/j.ijom.2006.01.021

[36]   Celeste, A.J., Song, J.J., Cox, K.A., Rosen, V. and Wozney, J.M. (1994) Bone morphogenetic protein-9, a new member of the TGF beta superfamily. Journal of Bone and Mineral Research, 9, 136.

[37]   Alden, T.D., Beres, E.J., Laurent, J.S., Engh, J.A., Das, S., London, S.D., Jane Jr., J.A., Hudson, S.B. and Helm, G.A. (2000) The use of bone morphogenetic protein gene therapy in craniofacial bone repair. Journal of Craniofacial Surgery, 11, 24-30.
http://dx.doi.org/10.1097/00001665-200011010-00005

[38]   Epstein, N.E. (2011) Pros, cons, and costs of INFUSE in spinal surgery. Surgical Neurology International, 2, 10.
http://dx.doi.org/10.4103/2152-7806.76147

[39]   Helm, G.A., Alden, T.D., Beres, E.J., Hudson, S.B., Das, S., Engh, J.A., Pittman, D.D., Kerns, K.M. and Kallmes, D.F. (2000) Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent. Journal of Neurosurgery, 92, 191-196.
http://dx.doi.org/10.3171/spi.2000.92.2.0191

[40]   Dumont, R.J., Dayoub, H., Li, J.Z., Dumont, A.S., Kallmes, D.F., Hankins, G.R. and Helm, G.A. (2002) Ex vivo bone morphogenetic protein-9 gene therapy using human mesenchymal stem cells induces spinal fusion in rodents. Neurosurgery, 51, 1239-1244.

[41]   Dayoub, H., Dumont, R.J., Li, J.Z., Dumont, A.S., Hankins, G.R., Kallmes, D.F. and Helm, G.A. (2003) Human mesenchymal stem cells transduced with recombinant bone morphogenetic protein-9 adenovirus promote osteogenesis in rodents. Tissue Engineering, 9, 347-356. http://dx.doi.org/10.1089/107632703764664819

[42]   Abdelaal, M.M., Tholpady, S.S., Kessler, J.D., Morgan, R.F. and Ogle, R.C. (2004) BMP-9-transduced prefabricated muscular flaps for the treatment of bony defects. Journal of Craniofacial Surgery, 15, 736-741.
http://dx.doi.org/10.1097/00001665-200409000-00007

[43]   Aslan, H., Zilberman, Y., Arbeli, V., Sheyn, D., Matan, Y., Liebergall, M., Li, J.Z., Helm, G.A., Gazit, D. and Gazit, Z. (2006) Nucleofection-based ex vivo nonviral gene delivery to human stem cells as a platform for tissue regeneration. Tissue Engineering, 12, 877-889.
http://dx.doi.org/10.1089/ten.2006.12.877

[44]   Itakura, K., Hirose, T., Crea, R., Riggs, A.D., Heyneker, H.L., Bolivar, F. and Boyer, H.W. (1977) Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin. Science, 198, 1056-1063.
http://dx.doi.org/10.1126/science.412251

[45]   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.
http://dx.doi.org/10.1210/en.136.10.4293

[46]   Chen, C., Grzegorzewski, K.J., Barash, S., Zhao, Q., Schneider, H., Wang, Q., et al. (2003) An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis. Nature Biotechnology, 21, 294-301.

[47]   Bessa, P.C., Cerqueira, M.T., Rada, T., Gomes, M.E., Neves, N.M., Nobre, A., Reis, R.L. and Casal, M. (2009) Expression, purification and osteogenic bioactivity of recombinant human BMP-4, -9, -10, -11 and -14. Protein Expression and Purification, 63, 89-94.
http://dx.doi.org/10.1016/j.pep.2008.09.014

[48]   Bergeron, E., Marquis, M.E., Chretien, I. and Faucheux, N. (2007) Differentiation of preosteoblasts using a delivery system with BMPs and bioactive glass microspheres. Journal of Materials Science: Materials in Medicine, 18, 255-263.
http://dx.doi.org/10.1007/s10856-006-0687-4

[49]   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.
http://dx.doi.org/10.1126/science.3201241

[50]   Glaser, D.L., Economides, A.N., Wang, L., Liu, X., Kimble, R.D., Fandl, J.P., Wilson, J.M., Stahl, N., Kaplan, F.S. and Shore, E.M. (2003) In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification. The Journal of Bone & Joint Surgery, 85-A, 2332-2342.

[51]   Clever, J.L., Sakai, Y., Wang, R.A. and Schneider, D.B. (2010) Inefficient skeletal muscle repair in inhibitor of differentiation knockout mice suggests a crucial role for BMP signaling during adult muscle regeneration. American Journal of Physiology, 298, C1087-C1099.
http://dx.doi.org/10.1152/ajpcell.00388.2009

[52]   Ono, Y., Calhabeu, F., Morgan, J.E., Katagiri, T., Amthor, H. and Zammit, P.S. (2010) BMP signalling permits population expansion by preventing premature myogenic differentiation in muscle satellite cells. Cell Death and Differentiation, 18, 222-234.
http://dx.doi.org/10.1038/cdd.2010.95

[53]   Katagiri, T., Yamaguchi, A., Komaki, M., Abe, E., Takahashi, N., Ikeda, T., Rosen, V., Wozney, J.M., Fujisawa-Sehara, A. and Suda, T. (1994) Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. The Journal of Cell Biology, 127, 1755-1766.
http://dx.doi.org/10.1083/jcb.127.6.1755

[54]   Oishi, T., Uezumi, A., Kanaji, A., Yamamoto, N., Yamaguchi, A., Yamada, H. and Tsuchida, K. (2013) Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS One, 8, e56641.
http://dx.doi.org/10.1371/journal.pone.0056641

[55]   Jackson, W.M., Aragon, A.B., Bulken-Hoover, J.D., Nesti, L.J. and Tuan, R.S. (2009) Putative heterotopic ossification progenitor cells derived from traumatized muscle. Journal of Orthopaedic Research, 27, 1645-1651.
http://dx.doi.org/10.1002/jor.20924

[56]   Leblanc, E., Trensz, F., Haroun, S., Drouin, G., Bergeron, E., Penton, C.M., Montanaro, F., Roux, S., Faucheux, N. and Grenier, G. (2011) BMP9-Induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment. Journal of Bone and Mineral Research, 26, 1166-1177.
http://dx.doi.org/10.1002/jbmr.311

[57]   Lauzon, M.A., Bergeron, E., Marcos, B. and Faucheux, N. (2012) Bone repair: New developments in growth factor delivery systems and their mathematical modeling. Journal of Controlled Release, 162, 502-520.
http://dx.doi.org/10.1016/j.jconrel.2012.07.041

[58]   Bergeron, E., Leblanc, E., Drevelle, O., Giguere, R., Beauvais, S., Grenier, G. and Faucheux, N. (2012) The evaluation of ectopic bone formation induced by delivery systems for bone morphogenetic protein-9 or its derived peptide. Tissue Engineering Part A, 18, 342-352.
http://dx.doi.org/10.1089/ten.tea.2011.0008

[59]   Bessa, P.C., Balmayor, E.R., Azevedo, H.S., Nurnberger, S., Casal, M., van Griensven, M., Reis, R.L. and Redl, H. (2010) Silk fibroin microparticles as carriers for delivery of human recombinant BMPs. Physical characterization and drug release. Journal of Tissue Engineering and Regenerative Medicine, 4, 349-355.

[60]   Drevelle, O., Daviau, A., Lauzon, M.A. and Faucheux, N. (2013) Effect of BMP-2 and/or BMP-9 on preosteoblasts attached to polycaprolactone functionalized by adhesive peptides derived from bone sialoprotein. Biomaterials, 34, 1051-1062.
http://dx.doi.org/10.1016/j.biomaterials.2012.10.066

[61]   Marquis, M.E., Lord, E., Bergeron, E., Bourgoin, L. and Faucheux, N. (2008) Short-term effects of adhesion peptides on the responses of preosteoblasts to pBMP-9. Biomaterials, 29, 1005-1016.
http://dx.doi.org/10.1016/j.biomaterials.2007.10.047

[62]   Miller, M.D. (2008) Review of orthopaedics. Saunders/ Elsevier, Philadelphia.

[63]   Goldring, M.B., Tsuchimochi, K. and Ijiri, K. (2005) The control of chondrogenesis. Journal of Cellular Biochemistry, 97, 33-44.
http://dx.doi.org/10.1002/jcb.20652

[64]   Hidaka, C. and Goldring, M.B. (2008) Regulatory mechanisms of chondrogenesis and implications for understanding articular cartilage homeostasis. Current Rheumatology Reviews, 4, 136-147.
http://dx.doi.org/10.2174/157339708785133541

[65]   Pizette, S. and Niswander, L. (2000) BMPs are required at two steps of limb chondrogenesis: Formation of prechondrogenic condensations and their differentiation into chondrocytes. Developmental Biology, 219, 237-249.
http://dx.doi.org/10.1006/dbio.2000.9610

[66]   Yoon, B.S., Ovchinnikov, D.A., Yoshii, I., Mishina, Y., Behringer, R.R. and Lyons, K.M. (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proceedings of the National Academy of Sciences of the United States of America, 102, 5062-5067.

[67]   Kramer, J., Hegert, C., Guan, K., Wobus, A.M., Muller, P.K. and Rohwedel, J. (2000) Embryonic stem cell-derived chondrogenic differentiation in vitro: Activation by BMP-2 and BMP-4. Mechanisms of Development, 92, 193-205.
http://dx.doi.org/10.1016/S0925-4773(99)00339-1

[68]   Chubinskaya, S. and Kuettner, K.E. (2003) Regulation of osteogenic proteins by chondrocytes. The International Journal of Biochemistry & Cell Biology, 35, 1323-1340.
http://dx.doi.org/10.1016/S1357-2725(03)00035-9

[69]   Yeh, L.C., Mallein-Gerin, F. and Lee, J.C. (2002) Differential effects of osteogenic protein-1 (BMP-7) on gene expression of BMP and GDF family members during differentiation of the mouse MC615 chondrocyte cells. Journal of Cellular Physiology, 191, 298-309.
http://dx.doi.org/10.1002/jcp.10094

[70]   Chubinskaya, S., Merrihew, C., Cs-Szabo, G., Mollenhauer, J., McCartney, J., Rueger, D.C. and Kuettner, K.E. (2000) Human articular chondrocytes express osteogenic protein-1. Journal of Histochemistry & Cytochemistry, 48, 239-250.

[71]   Varady, P., Li, J.Z., Cunningham, M., Beres, E.J., Das, S., Engh, J., Alden, T.D., Pittman, D.D., Kerns, K.M., Kallmes, D.F. and Helm, G.A. (2001) Morphologic analysis of BMP-9 gene therapy-induced osteogenesis. Human Gene Therapy, 12, 697-710.
http://dx.doi.org/10.1089/104303401300057423

[72]   Majumdar, M.K., Wang, E. and Morris, E.A. (2001) BMP-2 and BMP-9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL-1. Journal of Cellular Physiology, 189, 275-284.
http://dx.doi.org/10.1002/jcp.10025

[73]   Blunk, T., Sieminski, A.L., Appel, B., Croft, C., Courter, D.L., Chieh, J.J., Goepferich, A., Khurana, J.S. and Gooch, K.J. (2003) Bone morphogenetic protein 9: A potent modulator of cartilage development in vitro. Growth Factors, 21, 71-77.
http://dx.doi.org/10.1080/0897719031000148822

[74]   Fong, D., Bisson, M., Laberge, G., McManus, S., Grenier, G., Faucheux, N. and Roux, S. (2013) Bone morphogenetic protein-9 activates smad and ERK pathways and supports human osteoclast function and survival in vitro. Cellular Signalling, 25, 717-728.
http://dx.doi.org/10.1016/j.cellsig.2012.12.003

[75]   Castonguay, R., Werner, E.D., Matthews, R.G., Presman, E., Mulivor, A.W., Solban, N., et al. (2011) Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. The Journal of Biological Chemistry, 286, 30034-30046.
http://dx.doi.org/10.1074/jbc.M111.260133

[76]   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. Molecular Cancer Research, 6, 1594-1606.
http://dx.doi.org/10.1158/1541-7786.MCR-08-0171

[77]   Li, B., Yang, Y., Jiang, S., Ni, B., Chen, K. and Jiang, L. (2012) Adenovirus-mediated overexpression of BMP-9 inhibits human osteosarcoma cell growth and migration through downregulation of the PI3K/AKT pathway. International Journal of Oncology, 41, 1809-1819.

[78]   Cunha, S.I., Pardali, E., Thorikay, M., Anderberg, C., Hawinkels, L., Goumans, M.J., Seehra, J., Heldin, C.H., ten Dijke, P. and Pietras, K. (2010) Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis. The Journal of Experimental Medicine, 207, 85-100.

[79]   Suzuki, Y., Ohga, N., Morishita, Y., Hida, K., Miyazono, K. and Watabe, T. (2010) BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. Journal of Cell Science, 123, 1684-1692.

[80]   Luo, X., Chen, J., Song, W.X., Tang, N., Luo, J., Deng, Z.L., et al. (2008) Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects. Laboratory Investigation, 88, 1264-1277.
http://dx.doi.org/10.1038/labinvest.2008.98

[81]   Park, H., Drevelle, O., Daviau, A., Senta, H., Bergeron, E. and Faucheux, N. (2012) Preventing MEK1 activation influences the responses of human osteosarcoma cells to bone morphogenetic proteins 2 and 9. Anticancer Drugs, 24, 278-290.
http://dx.doi.org/10.1097/CAD.0b013e32835cbde7

[82]   Lv, Z., Yang, D., Li, J., Hu, M., Luo, M., Zhan, X., Song, P., Liu, C., Bai, H., Li, B., Yang, Y., Chen, Y., Shi, Q. and Weng, Y. (2013) Bone morphogenetic protein 9 overexpression reduces osteosarcoma cell migration and invasion. Molecules and Cells, 36, 119-126.
http://dx.doi.org/10.1007/s10059-013-0043-8

[83]   Spanjol, J., Djordjevic, G., Markic, D., Klaric, M., Fuckar, D. and Bobinac, D. (2010) Role of bone morphogenetic proteins in human prostate cancer pathogenesis and development of bone metastases: Immunohistochemical study. Collegium Antropologicum, 34, 119-125.

[84]   David, L., Feige, J.J. and Bailly, S. (2009) Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine & Growth Factor Reviews, 20, 203-212.
http://dx.doi.org/10.1016/j.cytogfr.2009.05.001

[85]   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. Molecular Cancer Therapy, 9, 379-388.
http://dx.doi.org/10.1158/1535-7163.MCT-09-0650

[86]   Ricard, N., Bidart, M., Mallet, C., Lesca, G., Giraud, S., Prudent, R., Feige, J.J. and Bailly, S. (2010) Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: A diagnostic tool for novel ACVRL1 mutations. Blood, 116, 1604-1612.

[87]   Herrera, B. and Inman, G.J. (2009) A rapid and sensitive bioassay for the simultaneous measurement of multiple bone morphogenetic proteins. Identification and quantification of BMP4, BMP6 and BMP9 in bovine and human serum. BMC Cell Biology, 10, 20.
http://dx.doi.org/10.1186/1471-2121-10-20

[88]   Haitjema, T., Westermann, C.J., Overtoom, T.T., Timmer, R., Disch, F., Mauser, H. and Lammers, J.W. (1996) Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): New insights in pathogenesis, complications, and treatment. Archives of Internal Medicine, 156, 714-719.
http://dx.doi.org/10.1001/archinte.1996.00440070028004

[89]   Mahmoud, M., Upton, P.D. and Arthur, H.M. (2011) Angiogenesis regulation by TGFbeta signalling: Clues from an inherited vascular disease. Biochemical Society Transactions, 39, 1659-1666.
http://dx.doi.org/10.1042/BST20110664

[90]   Alt, A., Miguel-Romero, L., Donderis, J., Aristorena, M., Blanco, F.J., Round, A., Rubio, V., Bernabeu, C. and Marina, A. (2012) Structural and functional insights into endoglin ligand recognition and binding. PLoS One, 7, e29948. http://dx.doi.org/10.1371/journal.pone.0029948

[91]   Bailly, S., Dupuis-Girod, S. and Plauchu, H. (2010) Rendu-osler disease: Clinical and molecular update. Medicine/Science (Paris), 26, 855-860.
http://dx.doi.org/10.1051/medsci/20102610855

[92]   Choi, E.J., Kim, Y.H., Choe, S.W., Tak, Y.G., GarridoMartin, E.M., Chang, M., Lee, Y.J. and Oh, S.P. (2013) Enhanced responses to angiogenic cues underlie the pathogenesis of hereditary hemorrhagic telangiectasia 2. PLoS One, 8, e63138.
http://dx.doi.org/10.1371/journal.pone.0063138

[93]   Somekawa, S., Imagawa, K., Hayashi, H., Sakabe, M., Ioka, T., Sato, G.E., Inada, K., Iwamoto, T., Mori, T., Ue-mura, S., Nakagawa, O. and Saito, Y. (2012) Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morpho genesis. Proceedings of the National Academy of Scien ces of the United States of America, 109, 12064-12069.

[94]   Chida, A., Shintani, M., Yagi, H., Fujiwara, M., Kojima, Y., Sato, H., et al. (2013) Outcomes of childhood pul monary arterial hypertension in BMPR2 and ALK1 mu tation carriers. American Journal of Cardiology, 110, 586-593.

[95]   Dunmore, B.J., Drake, K.M., Upton, P.D., Toshner, M.R., Aldred, M.A. and Morrell, N.W. (2013) The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations. Human Molecular Genetics, 22, 3667-3679

[96]   Bachiller, D., Klingensmith, J., Kemp, C., Belo, J.A., Anderson, R.M., May, S.R., McMahon, J.A., McMahon, A.P., Harland, R.M., Rossant, J. and De Robertis, E.M. (2000) The organizer factors chordin and noggin are required for mouse forebrain development. Nature, 403, 658-661.

[97]   Weinstein, D.C. and Hemmati-Brivanlou, A. (1999) Neural induction. Annual Review of Cell and Developmental Biology, 15, 411-433.
http://dx.doi.org/10.1146/annurev.cellbio.15.1.411

[98]   Lopez-Coviella, I., Mellott, T.M., Kovacheva, V.P., Berse, B., Slack, B.E., Zemelko, V., Schnitzler, A. and Blusztajn, J.K. (2006) Developmental pattern of expression of BMP receptors and smads and activation of Smad1 and Smad5 by BMP9 in mouse basal forebrain. Brain Research, 1088, 49-56.
http://dx.doi.org/10.1016/j.brainres.2006.02.073

[99]   Lopez-Coviella, I., Berse, B., Krauss, R., Thies, R.S. and Blusztajn, J.K. (2000) Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9. Science, 289, 313-316.
http://dx.doi.org/10.1016/j.brainres.2006.02.073

[100]   Wu, C.K., Thal, L., Pizzo, D., Hansen, L., Masliah, E. and Geula, C. (2005) Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer’s disease. Experimental Neurology, 195, 484-496.
http://dx.doi.org/10.1016/j.expneurol.2005.06.020

[101]   Lopez-Coviella, I., Follettie, M.T., Mellott, T.J., Kovacheva, V.P., Slack, B.E., Diesl, V., Berse, B., Thies, R.S. and Blusztajn, J.K. (2005) Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons. Proceedings of the National Academy of Sciences of the United States of America, 102, 6984-6989.

[102]   Lopez-Coviella, I., Mellott, T.J., Schnitzler, A.C. and Blusztajn, J.K. (2011) BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype. PLoS One, 6, e21166.
http://dx.doi.org/10.1371/journal.pone.0021166

[103]   Bissonnette, C.J., Lyass, L., Bhattacharyya, B.J., Belmadani, A., Miller, R.J. and Kessler, J.A. (2011) The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells. Stem Cells, 29, 802-811.
http://dx.doi.org/10.1002/stem.626

[104]   Citta-Pietrolungo, T.J., Alexander, M.A. and Steg, N.L. (1992) Early detection of heterotopic ossification in young patients with traumatic brain injury. Archives of Physical Medicine and Rehabilitation, 73, 258-262.

[105]   Gautschi, O.P., Cadosch, D., Frey, S.P., Skirving, A.P., Filgueira, L. and Zellweger, R. (2009) Serum-mediated osteogenic effect in traumatic brain-injured patients. ANZ Journal of Surgery, 79, 449-455.
http://dx.doi.org/10.1111/j.1445-2197.2008.04803.x

[106]   Cadosch, D., Gautschi, O.P., Thyer, M., Song, S., Skirving, A.P., Filgueira, L. and Zellweger, R. (2009) Humoral factors enhance fracture-healing and callus formation in patients with traumatic brain injury. The Journal of Bone & Joint Surgery, 91, 282-288.
http://dx.doi.org/10.2106/JBJS.G.01613

[107]   Cipriano, C.A., Pill, S.G. and Keenan, M.A. (2009) Heterotopic ossification following traumatic brain injury and spinal cord injury. Journal of the American Academy of Orthopaedic Surgeons, 17, 689-697.

[108]   Gautschi, O.P., Toffoli, A.M., Joesbury, K.A., Skirving, A.P., Filgueira, L. and Zellweger, R. (2007) Osteoinductive effect of cerebrospinal fluid from brain-injured patients. Journal of Neurotrauma, 24, 154-162.
http://dx.doi.org/10.1089/neu.2006.0166

[109]   Toffoli, A.M., Gautschi, O.P., Frey, S.P., Filgueira, L. and Zellweger, R. (2008) From brain to bone: Evidence for the release of osteogenic humoral factors after traumatic brain injury. Brain Injury, 22, 511-518.
http://dx.doi.org/10.1080/02699050802158235

[110]   Sosa, I., Cvijanovic, O., Celic, T., Cuculic, D., CrncevicOrlic, Z., Vukelic, L., Zoricic-Cvek, S., Dudaric, L., Bosnar, A. and Bobinac, D. (2011) Hepatoregenerative role of bone morphogenetic protein-9. Medical Science Monitor, 17, 33-35.
http://dx.doi.org/10.12659/MSM.882108

[111]   Gao, Y.L., Cai, X.F., Liu, J., Shan, X.L., Chen, Q.M., Zhou, F. and Tang, N. (2011) Hepatic lineage differentiation of hepatic progenitor cells by bone morphogenetic protein or leukemia inhibitory factor. Zhonghua Gan Zang Bing Za Zhi, 19, 692-695.

[112]   George, S., Rochford, J.J., Wolfrum, C., Gray, S.L., Schinner, S., Wilson, J.C., et al. (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science, 304, 1325-1328.

[113]   Cho, H., Mu, J., Kim, J.K., Thorvaldsen, J.L., Chu, Q., Crenshaw, E.B., 3rd, Kaestner, K.H., Bartolomei, M.S., Shulman, G.I. and Birnbaum, M.J. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science, 292, 1728-1731.

[114]   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. Molecular and Cellular Endocrinology, 319, 30-38.
http://dx.doi.org/10.1126/science.292.5522.1728

[115]   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.

 
 
Top