BMP signaling in mesenchymal stem cell differentiation and bone formation
Maureen Beederman, Joseph D. Lamplot, Guoxin Nan, Jinhua Wang, Xing Liu, Liangjun Yin, Ruidong Li, Wei Shui, Hongyu Zhang, Stephanie H. Kim, Wenwen Zhang, Jiye Zhang, Yuhan Kong, Sahitya Denduluri, Mary Rose Rogers, Abdullah Pratt, Rex C. Haydon, Hue H. Luu, Jovito Angeles, Lewis L. Shi, Tong-Chuan He
Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA.
Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics Co-Designated by Chinese Ministry of Education, The Children’s Hospital of Chongqing Medical University, Chongqing, China.
Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics Co-Designated by Chinese Ministry of Education, The Children’s Hospital of Chongqing Medical University, Chongqing, China The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
DOI: 10.4236/jbise.2013.68A1004   PDF    HTML     11,354 Downloads   16,623 Views   Citations

Abstract

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and have diverse functions during development and organogenesis. BMPs play a major role in skeletal development and bone formation, and disruptions in BMP signaling cause a variety of skeletal and extraskeletal anomalies. Several knockout models have provided insight into the mechanisms responsible for these phenotypes. Proper bone formation requires the differentiation of osteoblasts from mesenchymal stem cell (MSC) precursors, a process mediated in part by BMP signaling. Multiple BMPs, including BMP2, BMP6, BMP7 and BMP9, promote osteoblastic differentiation of MSCs both in vitro and in vivo. BMP9 is one of the most osteogenic BMPs, yet it is a poorly characterized member of the BMP family. Several studies demonstrate that the mechanisms controlling BMP9-mediated osteogenesis differ from other osteogenic BMPs, but little is known about these specific mechanisms. Several pathways critical to BMP9-mediated osteogenesis are also important in the differentiation of other cell lineages, including adipocytes and chondrocytes. BMP9 has also demonstrated translational promise in spinal fusion and bone fracture repair. This review will summarize our current knowledge of BMP-mediated osteogenesis, with a focus on BMP9, by presenting recently completed work which may help us to further elucidate these pathways.

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Beederman, M. , Lamplot, J. , Nan, G. , Wang, J. , Liu, X. , Yin, L. , Li, R. , Shui, W. , Zhang, H. , Kim, S. , Zhang, W. , Zhang, J. , Kong, Y. , Denduluri, S. , Rogers, M. , Pratt, A. , Haydon, R. , Luu, H. , Angeles, J. , Shi, L. and He, T. (2013) BMP signaling in mesenchymal stem cell differentiation and bone formation. Journal of Biomedical Science and Engineering, 6, 32-52. doi: 10.4236/jbise.2013.68A1004.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] [1] Attisano, L. and Wrana, J.L. (2002) Signal transduction by the TGF-beta superfamily. Science, 296, 1646-1647. doi:10.1126/science.1071809
[2] Hogan, B.L. (1996) Bone morphogenetic proteins in development. Current Opinion in Genetics & Development, 6, 432-438. doi:10.1016/S0959-437X(96)80064-5
[3] Shi, Y. and Massague, J. (2003) Mechanisms of TGFbeta signaling from cell membrane to the nucleus. Cell, 113, 685-700. doi:10.1016/S0092-8674(03)00432-X
[4] Varga, A.C. and Wrana, J.L. (2005) The disparate role of BMP in stem cell biology. Oncogene, 24, 5713-5721. doi:10.1038/sj.onc.1208919
[5] Zhang, J. and Li, L. (2005) BMP signaling and stem cell regulation. Developmental Biology, 284, 1-11. doi:10.1016/j.ydbio.2005.05.009
[6] Christiansen, J.H., Coles, E.G. and Wilkinson, D.G. (2000) Molecular control of neural crest formation, migration and differentiation. Current Opinion in Cell Biology, 12, 719-724. doi:10.1016/S0955-0674(00)00158-7
[7] Derynck, R. and Feng, X.H. (1997) TGF-beta receptor signaling. Biochimica et Biophysica Acta, 1333, F105-F150.
[8] Di Cesare, P.E., Frenkel, S.R., Carlson, C.S., Fang, C. and Liu, C. (2006) Regional gene therapy for full-thickness articular cartilage lesions using naked DNA with a collagen matrix. Journal of Orthopaedic Research, 24, 1118-1127.
[9] Hu, J., Chen, Y.X., Wang, D., Qi, X., Li, T.G., Hao, J., Mishina, Y., Garbers, D.L. and Zhao, G.Q. (2004) Developmental expression and function of Bmp4 in spermatogenesis and in maintaining epididymal integrity. Developmental Biology, 276, 158-171. doi:10.1016/j.ydbio.2004.08.034
[10] Kuo, A.C., Rodrigo, J.J., Reddi, A.H., Curtiss, S., Grotkopp, E. and Chiu, M. (2006) Microfracture and bone morphogenetic protein 7 (BMP-7) synergistically stimulate articular cartilage repair. Osteoarthritis and Cartilage, 14, 1126-1135. doi:10.1016/j.joca.2006.04.004
[11] Luu, H.H., Song, W.X., Luo, X., Manning, D., Luo, J., Deng, Z.L., Sharff, K.A., Montag, A.G., Haydon, R.C. and He, T.C. (2007) Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. Journal of Orthopaedic Research, 25, 665-677. doi:10.1002/jor.20359
[12] Mitu, G. and Hirschberg, R. (2008) Bone morphogenetic protein-7 (BMP7) in chronic kidney disease. Frontiers in Bioscience, 13, 4726-4739.
[13] Kang, Q., Sun, M.H., Cheng, H., Peng, Y., Montag, A.G., Deyrup, A.T., Jiang, W., Luu, H.H., Luo, J., Szatkowski, J.P., Vanichakarn, P., Park, J.Y., Li, Y., Haydon, R.C. and He, T.C. (2004) Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Therapy, 11, 1312-1320. doi:10.1038/sj.gt.3302298
[14] Luther, G., Wagner, E.R., Zhu, G., Kang, Q., Luo, Q., Lamplot, J., Bi, Y., Luo, X., Luo, J., Teven, C., Shi, Q., Kim, S.H., Gao, J.L., Huang, E., Yang, K., Rames, R., Liu, X., Li, M., Hu, N., Liu, H., Su, Y., Chen, L., He, B.C., Zuo, G.W., Deng, Z.L., Reid, R.R., Luu, H.H., Haydon, R.C. and He, T.C. (2011) BMP-9 induced osteogenic differentiation of mesenchymal stem cells: Molecular mechanism and therapeutic potential. Current Gene Therapy, 11, 229-240. doi:10.2174/156652311795684777
[15] Aubin, J.E. (2001) Regulation of osteoblast formation and function. Reviews in Endocrine and Metabolic Disorders, 2, 81-94. doi:10.1023/A:1010011209064
[16] Deng, Z.L., Sharff, K.A., Tang, N., Song, W.X., Luo, J., Luo, X., Chen, J., Bennett, E., Reid, R., Manning, D., Xue, A., Montag, A.G., Luu, H.H., Haydon, R.C. and He, T.C. (2008) Regulation of osteogenic differentiation during skeletal development. Frontiers in Bioscience, 13, 2001-2021. doi:10.2741/2819
[17] He, B.C., Chen, L., Zuo, G.W., Zhang, W., Bi, Y., Huang, J., Wang, Y., Jiang, W., Luo, Q., Shi, Q., Zhang, B.Q., Liu, B., Lei, X., Luo, J., Luo, X., Wagner, E.R., Kim, S.H., He, C.J., Hu, Y., Shen, J., Zhou, Q., Rastegar, F., Deng, Z.L., Luu, H.H., He, T.C. and Haydon, R.C. (2010) Synergistic antitumor effect of the activated PPAR-gamma and retinoid receptors on human osteosarcoma. Clinical Cancer Research, 16, 2235-2245. doi:10.1158/1078-0432.CCR-09-2499
[18] Kang, Q., Song, W.X., Luo, Q., Tang, N., Luo, J., Luo, X., Chen, J., Bi, Y., He, B.C., Park, J.K., Jiang, W., Tang, Y., Huang, J., Su, Y., Zhu, G.H., He, Y., Yin, H., Hu, Z., Wang, Y., Chen, L., Zuo, G.W., Pan, X., Shen, J., Vokes, T., Reid, R.R., Haydon, R.C., Luu, H.H. and He, T.C. (2009) A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differenttiation of mesenchymal progenitor cells. Stem Cells and Development, 18, 545-559. doi:10.1089/scd.2008.0130
[19] Urist, M.R. (1965) Bone: Formation by autoinduction. Science, 150, 893-899. doi:10.1126/science.150.3698.893
[20] 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. doi:10.1126/science.3201241
[21] Hogan, B.L. (1996) Bone morphogenetic proteins: Multifunctional regulators of vertebrate development. Genes & Development, 10, 1580-1594. doi:10.1101/gad.10.13.1580
[22] Zhao, G.Q. (2003) Consequences of knocking out BMP signaling in the mouse. Genesis, 35, 43-56. doi:10.1002/gene.10167
[23] 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. doi:10.1210/en.136.10.4293
[24] 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. Nature Biotechnology, 21, 294-301.
[25] 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. doi:10.1126/science.289.5477.313
[26] Truksa, J., Peng, H., Lee, P. and Beutler, E. (2006) Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proceedings of the National Academy of Sciences of the United States of America, 103, 10289-10293. doi:10.1073/pnas.0603124103
[27] Cheng, H., Jiang, W., Phillips, F.M., Haydon, R.C., Peng, Y., Zhou, L., Luu, H.H., An, N., Breyer, B., Vanichakarn, P., Szatkowski, J.P., Park, J.Y. and He, T.C. (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). The Journal of Bone and Joint Surgery. American Volume, 85-A, 1544-1552.
[28] Luo, Q., Kang, Q., Si, W., Jiang, W., Park, J.K., Peng, Y., Li, X., Luu, H.H., Luo, J., Montag, A.G., Haydon, R.C. and He, T.C. (2004) Connective tissue growth factor (CTGF) is regulated by wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells. The Journal of Biological Chemistry, 279, 55958-55968. doi:10.1074/jbc.M407810200
[29] Peng, Y., Kang, Q., Cheng, H., Li, X., Sun, M.H., Jiang, W., Luu, H.H., Park, J.Y., Haydon, R.C. and He, T.C. (2003) Transcriptional characterization of bone morphogenetic proteins (BMPs)-mediated osteogenic signaling. Journal of Cellular Biochemistry, 90, 1149-1165. doi:10.1002/jcb.10744
[30] Peng, Y., Kang, Q., Luo, Q., Jiang, W., Si, W., Liu, B.A., Luu, H.H., Park, J.K., Li, X., Luo, J., Montag, A.G., Haydon, R.C. and He, T.C. (2004) Inhibitor of DNA binding/differentiation helix-loop-helix proteins mediate bone morphogenetic protein-induced osteoblast differentiation of mesenchymal stem cells. The Journal of Biological Chemistry, 279, 32941-32949. doi:10.1074/jbc.M403344200
[31] Karsenty, G. (1999) The genetic transformation of bone biology. Genes & Development, 13, 3037-3051. doi:10.1101/gad.13.23.3037
[32] Lian, J.B., Stein, G.S., Stein, J.L. and van Wijnen, A.J. (1998) Transcriptional control of osteoblast differentiation. Biochemical Society Transactions, 26, 14-21.
[33] Reddi, A.H. (1997) Bone morphogenetic proteins: An unconventional approach to isolation of first mammalian morphogens. Cytokine & Growth Factor Reviews, 8, 11-20. doi:10.1016/S1359-6101(96)00049-4
[34] Lin, G.L. and Hankenson, K.D. (2011) Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. Journal of Cellular Biochemistry, 112, 3491-3501. doi:10.1002/jcb.23287
[35] Marcellini, S., Henriquez, J.P. and Bertin, A. (2012) Control of osteogenesis by the canonical Wnt and BMP pathways in vivo: Cooperation and antagonism between the canonical Wnt and BMP pathways as cells differentiate from osteochondroprogenitors to osteoblasts and osteocytes. Bioessays, 34, 953-962. doi:10.1002/bies.201200061
[36] Olsen, B.R., Reginato, A.M. and Wang, W. (2000) Bone development. Annual Review of Cell and Developmental Biology, 16, 191-220. doi:10.1146/annurev.cellbio.16.1.191
[37] Ducy, P. and Karsenty, G. (2000) The family of bone morphogenetic proteins. Kidney International, 57, 2207-2214. doi:10.1046/j.1523-1755.2000.00081.x
[38] Ducy, P., Starbuck, M., Priemel, M., Shen, J., Pinero, G., Geoffroy, V., Amling, M. and Karsenty, G. (1999) A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes & Development, 13, 1025-1036. doi:10.1101/gad.13.8.1025
[39] Reddi, A.H. (1998) Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nature Biotechnology, 16, 247-252.
[40] Harada, S. and Rodan, G.A. (2003) Control of osteoblast function and regulation of bone mass. Nature, 423, 349-355.
[41] Ralston, S.H. and de Crombrugghe, B. (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes & Development, 20, 2492-2506. doi:10.1101/gad.1449506
[42] King, J.A., Marker, P.C., Seung, K.J. and Kingsley, D.M. (1994) BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Developmental Biology, 166, 112-122. doi:10.1006/dbio.1994.1300
[43] Hall, P.A. and Watt, F.M. (1989) Stem cells: The generation and maintenance of cellular diversity. Development, 106, 619-633.
[44] Tsumaki, N. and Yoshikawa, H. (2005) The role of bone morphogenetic proteins in endochondral bone formation. Cytokine & Growth Factor Reviews, 16, 279-285. doi:10.1016/j.cytogfr.2005.04.001
[45] Wu, N., Zhao, Y., Yin, Y., Zhang, Y. and Luo, J. (2010) Identification and analysis of type II TGF-beta recaptors in BMP-9-induced osteogenic differentiation of C3H10T1/2 mesenchymal stem cells. Acta Biochimica et Biophysica Sinica, 42, 699-708. doi:10.1093/abbs/gmq075
[46] Wu, X., Shi, W. and Cao, X. (2007) Multiplicity of BMP signaling in skeletal development. Annals of the New York Academy of Sciences, 1116, 29-49. doi:10.1196/annals.1402.053
[47] Shu, B., Zhang, M., Xie, R., Wang, M., Jin, H., Hou, W., Tang, D., Harris, S.E., Mishina, Y., O’Keefe, R.J., Hilton, M.J., Wang, Y. and Chen, D. (2011) BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development. Journal of Cell Science, 124, 3428-3440. doi:10.1242/jcs.083659
[48] Estrada, K.D., Retting, K.N., Chin, A.M. and Lyons, K.M. (2011) Smad6 is essential to limit BMP signaling during cartilage development. Journal of Bone and Mineral Research, 26, 2498-2510.
[49] Pan, Q., Yu, Y., Chen, Q., Li, C., Wu, H., Wan, Y., Ma, J. and Sun, F. (2008) Sox9, a key transcription factor of bone morphogenetic protein-2-induced chondrogenesis, is activated through BMP pathway and a CCAAT box in the proximal promoter. Journal of Cellular Physiology, 217, 228-241. doi:10.1002/jcp.21496
[50] Zehentner, B.K., Dony, C. and Burtscher, H. (1999) The transcription factor Sox9 is involved in BMP-2 signaling. Journal of Bone and Mineral Research, 14, 1734-1741. doi:10.1359/jbmr.1999.14.10.1734
[51] Wang, M., Jin, H., Tang, D., Huang, S., Zuscik, M.J. and Chen, D. (2011) Smad1 plays an essential role in bone development and postnatal bone formation. Osteoarthritis and Cartilage, 19, 751-762. doi:10.1016/j.joca.2011.03.004
[52] Yoon, B.S. and Lyons, K.M. (2004) Multiple functions of BMPs in chondrogenesis. Journal of Cellular Biochemistry, 93, 93-103. doi:10.1002/jcb.20211
[53] Canalis, E., Brunet, L.J., Parker, K. and Zanotti, S. (2012) Conditional inactivation of noggin in the postnatal skeleton causes osteopenia. Endocrinology, 153, 1616-1626. doi:10.1210/en.2011-1604
[54] Smith, W.C. and Harland, R.M. (1992) Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell, 70, 829-840. doi:10.1016/0092-8674(92)90316-5
[55] Valenzuela, D.M., Economides, A.N., Rojas, E., Lamb, T.M., Nunez, L., Jones, P., Lp, N.Y., Espinosa 3rd, R., Brannan, C.I., Gilbert, D.J., et al. (1995) Identification of mammalian noggin and its expression in the adult nervous system. The Journal of Neuroscience, 15, 6077-6084.
[56] Zimmerman, L.B., De Jesus-Escobar, J.M. and Harland, R.M. (1996) The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell, 86, 599-606. doi:10.1016/S0092-8674(00)80133-6
[57] Devlin, R.D., Du, Z., Pereira, R.C., Kimble, R.B., Economides, A.N., Jorgetti, V. and Canalis, E. (2003) Skeletal overexpression of noggin results in osteopenia and reduced bone formation. Endocrinology, 144, 1972-1978. doi:10.1210/en.2002-220918
[58] Brunet, L.J., McMahon, J.A., McMahon, A.P. and Harland, R.M. (1998) Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science, 280, 1455-1457. doi:10.1126/science.280.5368.1455
[59] Kamiya, N., Kobayashi, T., Mochida, Y., Yu, P.B., Yamauchi, M., Kronenberg, H.M. and Mishina, Y. (2009) Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. Journal of Bone and Mineral Research, 25, 200-210. doi:10.1359/jbmr.090806
[60] Kamiya, N., Ye, L., Kobayashi, T., Lucas, D.J., Mochida, Y., Yamauchi, M., Kronenberg, H.M., Feng, J.Q. and Mishina, Y. (2008) Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. Journal of Bone and Mineral Research, 23, 2007-2017. doi:10.1359/jbmr.080809
[61] Kamiya, N., Ye, L., Kobayashi, T., Mochida, Y., Yamauchi, M., Kronenberg, H.M., Feng, J.Q. and Mishina, Y. (2008) BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development, 135, 3801-3811. doi:10.1242/dev.025825
[62] Zhao, M., Harris, S.E., Horn, D., Geng, Z., Nishimura, R., Mundy, G.R. and Chen, D. (2002) Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. Journal of Cellular Biochemistry, 157, 1049-1060. doi:10.1083/jcb.200109012
[63] Francis-West, P.H., Tatla, T. and Brickell, P.M. (1994) Expression patterns of the bone morphogenetic protein genes Bmp-4 and Bmp-2 in the developing chick face suggest a role in outgrowth of the primordia. Developmental Dynamics, 201, 168-178. doi:10.1002/aja.1002010207
[64] Wan, C., Shao, J., Gilbert, S.R., Riddle, R.C., Long, F., Johnson, R.S., Schipani, E. and Clemens, T.L. (2010) Role of HIF-1alpha in skeletal development. Annals of the New York Academy of Sciences, 1192, 322-326. doi:10.1111/j.1749-6632.2009.05238.x
[65] Kanzler, B., Foreman, R.K., Labosky, P.A. and Mallo, M. (2000) BMP signaling is essential for development of skeletogenic and neurogenic cranial neural crest. Development, 127, 1095-1104.
[66] Luo, J., Tang, M., Huang, J., He, B.C., Gao, J.L., Chen, L., Zuo, G.W., Zhang, W., Luo, Q., Shi, Q., Zhang, B.Q., Bi, Y., Luo, X., Jiang, W., Su, Y., Shen, J., Kim, S.H., Huang, E., Gao, Y., Zhou, J.Z., Yang, K., Luu, H.H., Pan, X., Haydon, R.C., Deng, Z.L. and He, T.C. (2010) TGFbeta/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells. The Journal of Biological Chemistry, 285, 29588-29598. doi:10.1074/jbc.M110.130518
[67] Dudas, M., Sridurongrit, S., Nagy, A., Okazaki, K. and Kaartinen, V. (2004) Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells. Mechanisms of Development, 121, 173-182. doi:10.1016/j.mod.2003.12.003
[68] Bandyopadhyay, A., Tsuji, K., Cox, K., Harfe, B.D., Rosen, V. and Tabin, C.J. (2006) Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genetics, 2, e216. doi:10.1371/journal.pgen.0020216
[69] Dudley, A.T., Lyons, K.M. and Robertson, E.J. (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes & Development, 9, 2795-2807. doi:10.1101/gad.9.22.2795
[70] Luo, G., Hofmann, C., Bronckers, A.L., Sohocki, M., Bradley, A. and Karsenty, G. (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes & Development, 9, 2808-2820. doi:10.1101/gad.9.22.2808
[71] Solloway, M.J., Dudley, A.T., Bikoff, E.K., Lyons, K.M., Hogan, B.L. and Robertson, E.J. (1998) Mice lacking Bmp6 function. Developmental Genetics, 22, 321-339. doi:10.1002/(SICI)1520-6408(1998)22:4<321::AID-DVG3>3.0.CO;2-8
[72] McPherron, A.C., Lawler, A.M. and Lee, S.J. (1999) Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nature Genetics, 22, 260-264. doi:10.1038/10320
[73] Daluiski, A., Engstrand, T., Bahamonde, M.E., Gamer, L.W., Agius, E., Stevenson, S.L., Cox, K., Rosen, V. and Lyons, K.M. (2001) Bone morphogenetic protein-3 is a negative regulator of bone density. Nature Genetics, 27, 84-88. doi:10.1038/83810
[74] Winnier, G., Blessing, M., Labosky, P.A. and Hogan, B.L. (1995) Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes & Development, 9, 2105-2116. doi:10.1101/gad.9.17.2105
[75] Alden, T.D., Pittman, D.D., Beres, E.J., Hankins, G.R., Kallmes, D.F., Wisotsky, B.M., Kerns, K.M. and Helm, G.A. (1999) Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy. Journal of Neurosurgery, 90, 109-114.
[76] Alden, T.D., Pittman, D.D., Hankins, G.R., Beres, E.J., Engh, J.A., Das, S., Hudson, S.B., Kerns, K.M., Kallmes, D.F. and Helm, G.A. (1999) In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector. Human Gene Therapy, 10, 2245-2253. doi:10.1089/10430349950017220
[77] Baltzer, A.W., Lattermann, C., Whalen, J.D., Ghivizzani, S., Wooley, P., Krauspe, R., Robbins, P.D. and Evans, C.H. (2000) Potential role of direct adenoviral gene transfer in enhancing fracture repair. Clinical Orthopaedics and Related Research, S120-S125.
[78] Baltzer, A.W., Lattermann, C., Whalen, J.D., Wooley, P., Weiss, K., Grimm, M., Ghivizzani, S.C., Robbins, P.D. and Evans, C.H. (2000) Genetic enhancement of fracture repair: Healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Therapy, 7, 734-739. doi:10.1038/sj.gt.3301166
[79] Bosch, P., Musgrave, D., Ghivizzani, S., Latterman, C., Day, C.S. and Huard, J. (2000) The efficiency of musclederived cell-mediated bone formation. Cell Transplant, 9, 463-470.
[80] Breitbart, A.S., Grande, D.A., Mason, J.M., Barcia, M., James, T. and Grant, R.T. (1999) Gene-enhanced tissue engineering: Applications for bone healing using cultured periosteal cells transduced retrovirally with the BMP-7 gene. Annals of Plastic Surgery, 42, 488-495. doi:10.1097/00000637-199905000-00005
[81] Franceschi, R.T., Wang, D., Krebsbach, P.H. and Rutherford, R.B. (2000) Gene therapy for bone formation: In vitro and in vivo osteogenic activity of an adenovirus expressing BMP7. Journal of Cellular Biochemistry, 78, 476-486. doi:10.1002/1097-4644(20000901)78:3<476::AID-JCB12>3.0.CO;2-5
[82] Gazit, D., Turgeman, G., Kelley, P., Wang, E., Jalenak, M., Zilberman, Y. and Moutsatsos, I. (1990) Engineered pluripotent mesenchymal cells integrate and differentiate in regenerating bone: A novel cell-mediated gene therapy. The Journal of Gene Medicine, 1, 121-133. doi:10.1002/(SICI)1521-2254(199903/04)1:2<121::AID-JGM26>3.0.CO;2-J
[83] Krebsbach, P.H., Gu, K., Franceschi, R.T. and Rutherford, R.B. (2000) Gene therapy-directed osteogenesis: BMP-7transduced human fibroblasts form bone in vivo. Human Gene Therapy, 11, 1201-1210. doi:10.1089/10430340050015248
[84] Lee, J.Y., Musgrave, D., Pelinkovic, D., Fukushima, K., Cummins, J., Usas, A., Robbins, P., Fu, F.H. and Huard, J. (2001) Effect of bone morphogenetic protein-2-expressing muscle-derived cells on healing of critical-sized bone defects in mice. The Journal of Bone and Joint Surgery. American Volume, 83-A, 1032-1039.
[85] Lieberman, J.R., Le, L.Q., Wu, L., Finerman, G.A., Berk, A., Witte, O.N. and Stevenson, S. (1998) Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. Journal of Orthopaedic Research, 16, 330-339. doi:10.1002/jor.1100160309
[86] Lou, J., Xu, F., Merkel, K. and Manske, P. (1999) Gene therapy: Adenovirus-mediated human bone morphogenetic protein-2 gene transfer induces mesenchymal progenitor cell proliferation and differentiation in vitro and bone formation in vivo. Journal of Orthopaedic Research, 17, 43-50. doi:10.1002/jor.1100170108
[87] Mason, J.M., Grande, D.A., Barcia, M., Grant, R., Pergolizzi, R.G. and Breitbart, A.S. (1998) Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: Potential utility in gene therapy for osteochondral repair. Gene Therapy, 5, 1098-1104. doi:10.1038/sj.gt.3300703
[88] Musgrave, D.S., Bosch, P., Ghivizzani, S., Robbins, P.D., Evans, C.H. and Huard, J. (1999) Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone, 24, 541-547. doi:10.1016/S8756-3282(99)00086-1
[89] Okubo, Y., Bessho, K., Fujimura, K., Iizuka, T. and Miyatake, S.I. (2000) Osteoinduction by bone morphogenetic protein-2 via adenoviral vector under transient immunosuppression. Biochemical and Biophysical Research Communications, 267, 382-387. doi:10.1006/bbrc.1999.1975
[90] Oyama, M., Tatlock, A., Fukuta, S., Kavalkovich, K., Nishimura, K., Johnstone, B., Robbins, P.D., Evans, C.H. and Niyibizi, C. (1999) Retrovirally transduced bone marrow stromal cells isolated from a mouse model of human osteogenesis imperfecta (oim) persist in bone and retain the ability to form cartilage and bone after extended passaging. Gene Therapy, 6, 321-329. doi:10.1038/sj.gt.3300839
[91] Riew, K.D., Wright, N.M., Cheng, S., Avioli, L.V. and Lou, J. (1998) Induction of bone formation using a recombinant adenoviral vector carrying the human BMP-2 gene in a rabbit spinal fusion model. Calcified Tissue International, 63, 357-360. doi:10.1007/s002239900540
[92] Ripamonti, U., Ramoshebi, L.N., Matsaba, T., Tasker, J., Crooks, J. and Teare, J. (2001) Bone induction by BMPs/OPs and related family members in primates. The Journal of Bone and Joint Surgery. American Volume, 83-A, S116-S127.
[93] Sandhu, H.S., Khan, S.N., Suh, D.Y. and Boden, S.D. (2001) Demineralized bone matrix, bone morphogenetic proteins, and animal models of spine fusion: An overview. European Spine Journal, 10, S122-S131. doi:10.1007/s005860100303
[94] 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. doi:10.1089/104303401300057423
[95] Whang, K., Tsai, D.C., Nam, E.K., Aitken, M., Sprague, S.M., Patel, P.K. and Healy, K.E. (1998) Ectopic bone formation via rhBMP-2 delivery from porous bioabsorbable polymer scaffolds. Journal of Biomedical Materials Research, 42, 491-499. doi:10.1002/(SICI)1097-4636(19981215)42:4<491::AID-JBM3>3.0.CO;2-F
[96] He, T.C. (2005) Distinct osteogenic activity of BMPs and their orthopaedic applications. Journal of Musculoskeletal & Neuronal Interactions, 5, 363-366.
[97] Lian, J.B., Stein, G.S., Javed, A., van Wijnen, A.J., Stein, J.L., Montecino, M., Hassan, M.Q., Gaur, T., Lengner, C.J. and Young, D.W. (2006) Networks and hubs for the transcriptional control of osteoblastogenesis. Reviews in Endocrine and Metabolic Disorders, 7, 1-16. doi:10.1007/s11154-006-9001-5
[98] Yamaguchi, A., Komori, T. and Suda, T. (2000) Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocrine Reviews, 21, 393-411. doi:10.1210/er.21.4.393
[99] Cheng, S.L., Lou, J., Wright, N.M., Lai, C.F., Avioli, L.V. and Riew, K.D. (2001) In vitro and in vivo induction of bone formation using a recombinant adenoviral vector carrying the human BMP-2 gene. Calcified Tissue International, 68, 87-94. doi:10.1007/BF02678146
[100] Partridge, K., Yang, X., Clarke, N.M., Okubo, Y., Bessho, K., Sebald, W., Howdle, S.M., Shakesheff, K.M. and Oreffo, R.O. (2002) Adenoviral BMP-2 gene transfer in mesenchymal stem cells: In vitro and in vivo bone formation on biodegradable polymer scaffolds. Biochemical and Biophysical Research Communications, 292, 144-152. doi:10.1006/bbrc.2002.6623
[101] Yang, M., Ma, Q.J., Dang, G.T., Ma, K., Chen, P. and Zhou, C.Y. (2005) In vitro and in vivo induction of bone formation based on ex vivo gene therapy using rat adipose-derived adult stem cells expressing BMP-7. Cytotherapy, 7, 273-281. doi:10.1080/14653240510027244
[102] Varady, P., Li, J.Z., Alden, T.D., Kallmes, D.F., Williams, M.B. and Helm, G.A. (2002) CT and radionuclide study of BMP-2 gene therapy-induced bone formation. Academic Radiology, 9, 632-637. doi:10.1016/S1076-6332(03)80307-0
[103] Cook, S.D., Baffes, G.C., Wolfe, M.W., Sampath, T.K. and Rueger, D.C. (1994) Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clinical Orthopaedics and Related Research, 301, 302-312.
[104] Gerhart, T.N., Kirker-Head, C.A., Kriz, M.J., Holtrop, M.E., Hennig, G.E., Hipp, J., Schelling, S.H. and Wang, E. (1993) Healing segmental femoral defects in sheep using recombinant human bone morphogenetic protein. Clinical Orthopaedics and Related Research, 293, 317-326.
[105] Katagiri, T., Yamaguchi, A., Ikeda, T., Yoshiki, S., Wozney, J.M., Rosen, V., Wang, E.A., Tanaka, H., Omura, S. and Suda, T. (1990) The non-osteogenic mouse pluripotent cell line, C3H10T1/2, is induced to differentiate into osteoblastic cells by recombinant human bone morphogenetic protein-2. Biochemical and Biophysical Research Communications, 172, 295-299. doi:10.1016/S0006-291X(05)80208-6
[106] Valentin-Opran, A., Wozney, J., Csimma, C., Lilly, L. and Riedel, G.E. (2002) Clinical evaluation of recombinant human bone morphogenetic protein-2. Clinical Orthopaedics and Related Research, 395, 110-120. doi:10.1097/00003086-200202000-00011
[107] Yamaguchi, A., Katagiri, T., Ikeda, T., Wozney, J.M., Rosen, V., Wang, E.A., Kahn, A.J., Suda, T. and Yoshiki, S. (1991) Recombinant human bone morphogenetic protein-2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro. Journal of Cell Biology, 113, 681-687. doi:10.1083/jcb.113.3.681
[108] Yasko, A.W., Lane, J.M., Fellinger, E.J., Rosen, V., Wozney, J.M. and Wang, E.A. (1992) The healing of segmental bone defects, induced by recombinant human bone morphogenetic protein (rhBMP-2). A radiographic, histological, and biomechanical study in rats. The Journal of Bone and Joint Surgery. American Volume, 74, 659-670.
[109] Boden, S.D., Zdeblick, T.A., Sandhu, H.S. and Heim, S.E. (2000) The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: A preliminary report. Spine, 25, 376-381.
[110] Govender, S., Csimma, C., Genant, H.K., Valentin-Opran, A., Amit, Y., Arbel, R., Aro, H., Atar, D., Bishay, M., Borner, M.G., Chiron, P., Choong, P., Cinats, J., Courtenay, B., Feibel, R., Geulette, B., Gravel, C., Haas, N., Raschke, M., Hammacher, E., van der Velde, D., Hardy, P., Holt, M., Josten, C., Ketterl, R.L., Lindeque, B., Lob, G., Mathevon, H., McCoy, G., Marsh, D., Miller, R., Munting, E., Oevre, S., Nordsletten, L., Patel, A., Pohl, A., Rennie, W., Reynders, P., Rommens, P.M., Rondia, J., Rossouw, W.C., Daneel, P.J., Ruff, S., Ruter, A., Santavirta, S., Schildhauer, T.A., Gekle, C., Schnettler, R., Segal, D., Seiler, H., Snowdowne, R.B., Stapert, J., Taglang, G., Verdonk, R., Vogels, L., Weckbach, A., Wentzensen, A. and Wisniewski, T. (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: A prospective, controlled, randomized study of four hundred and fifty patients. The Journal of Bone and Joint Surgery. American Volume, 84-A, 2123-2134.
[111] Bostrom, M.P. and Camacho, N.P. (1998) Potential role of bone morphogenetic proteins in fracture healing. Clinical Orthopaedics and Related Research, 355S, S274-S282.
[112] Heckman, J.D., Boyan, B.D., Aufdemorte, T.B. and Abbott, J.T. (1991) The use of bone morphogenetic protein in the treatment of non-union in a canine model. The Journal of Bone and Joint Surgery. American Volume, 73, 750-764.
[113] 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.
[114] Lee, A.R., Wilkins, A.C., Leather, C. and Brenton, A.G. (1994) Translational energy spectra for single-electron capture by O2+ in He, Ne, and Ar. Physical Review A, 50, 1149-1154. doi:10.1103/PhysRevA.50.1149
[115] Luo, J., Sun, M.H., Kang, Q., Peng, Y., Jiang, W., Luu, H.H., Luo, Q., Park, J.Y., Li, Y., Haydon, R.C. and He, T.C. (2005) Gene therapy for bone regeneration. Current Gene Therapy, 5, 167-179. doi:10.2174/1566523053544218
[116] Tang, N., Song, W.X., Luo, J., Haydon, R.C. and He, T.C. (2008) Osteosarcoma development and stem cell differrentiation. Clinical Orthopaedics and Related Research, 466, 2114-2130. doi:10.1007/s11999-008-0335-z
[117] Wagner, E.R., He, B.C., Chen, L., Zuo, G.W., Zhang, W., Shi, Q., Luo, Q., Luo, X., Liu, B., Luo, J., Rastegar, F., He, C.J., Hu, Y., Boody, B., Luu, H.H., He, T.C., Deng, Z.L. and Haydon, R.C. (2010) Therapeutic implications of PPARgamma in human osteosarcoma. PPAR Research, 2010, 956427.
[118] Bertone, A.L., Pittman, D.D., Bouxsein, M.L., Li, J., Clancy, B. and Seeherman, H.J. (2004) Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model. Journal of Orthopaedic Research, 22, 1261-1270. doi:10.1016/j.orthres.2004.03.014
[119] Boden, S.D., Hair, G., Titus, L., Racine, M., McCuaig, K., Wozney, J.M. and Nanes, M.S. (1997) Glucocorticoidinduced differentiation of fetal rat calvarial osteoblasts is mediated by bone morphogenetic protein-6. Endocrinology, 138, 2820-2828. doi:10.1210/en.138.7.2820
[120] Boskey, A.L., Paschalis, E.P., Binderman, I. and Doty, S.B. (2002) BMP-6 accelerates both chondrogenesis and mineral maturation in differentiating chick limb-bud mesenchymal cell cultures. Journal of Cellular Biochemistry, 84, 509-519. doi:10.1002/jcb.10032
[121] Ebisawa, T., Tada, K., Kitajima, I., Tojo, K., Sampath, T.K., Kawabata, M., Miyazono, K. and Imamura, T. (1999) Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. Journal of Cell Science, 112, 3519-3527.
[122] Friedman, M.S., Long, M.W. and Hankenson, K.D. (2006) Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6. Journal of Cellular Biochemistry, 98, 538-554. doi:10.1002/jcb.20719
[123] Hughes, F.J., Collyer, J., Stanfield, M. and Goodman, S.A. (1995) The effects of bone morphogenetic protein-2,-4, and-6 on differentiation of rat osteoblast cells in vitro. Endocrinology, 136, 2671-2677. doi:10.1210/en.136.6.2671
[124] Jane Jr., J.A., Dunford, B.A., Kron, A., Pittman, D.D., Sasaki, T., Li, J.Z., Li, H., Alden, T.D., Dayoub, H., Hankins, G.R., Kallmes, D.F. and Helm, G.A. (2002) Ectopic osteogenesis using adenoviral bone morphogenetic protein (BMP)-4 and BMP-6 gene transfer. Molecular Therapy, 6, 464-470. doi:10.1006/mthe.2002.0691
[125] Valdes, M., Moore, D.C., Palumbo, M., Lucas, P.R., Robertson, A., Appel, J., Ehrlich, M.G. and Keeping, H.S. (2007) rhBMP-6 stimulated osteoprogenitor cells enhance posterolateral spinal fusion in the New Zealand white rabbit. The Spine Journal, 7, 318-325. doi:10.1016/j.spinee.2006.02.005
[126] Visser, R., Arrabal, P.M., Santos-Ruiz, L., Becerra, J. and Cifuentes, M. (2012) Basic fibroblast growth factor enhances the osteogenic differentiation induced by bone morphogenetic protein-6 in vitro and in vivo. Cytokine, 58, 27-33. doi:10.1016/j.cyto.2011.12.020
[127] Yamaguchi, A., Ishizuya, T., Kintou, N., Wada, Y., Katagiri, T., Wozney, J.M., Rosen, V. and Yoshiki, S. (1996) Effects of BMP-2, BMP-4, and BMP-6 on osteoblastic differentiation of bone marrow-derived stromal cell lines, ST2 and MC3T3-G2/PA6. Biochemical and Biophysical Research Communications, 220, 366-371. doi:10.1006/bbrc.1996.0411
[128] Zachos, T.A., Shields, K.M. and Bertone, A.L. (2006) Gene-mediated osteogenic differentiation of stem cells by bone morphogenetic proteins-2 or-6. Journal of Orthopaedic Research, 24, 1279-1291. doi:10.1002/jor.20068
[129] 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. doi:10.1089/ten.2006.12.877
[130] Santos, J.L., Pandita, D., Rodrigues, J., Pego, A.P., Granja, P.L. and Tomas, H. (2011) Non-viral gene delivery to mesenchymal stem cells: Methods, strategies and application in bone tissue engineering and regeneration. Current Gene Therapy, 11, 46-57. doi:10.2174/156652311794520102
[131] Sheyn, D., Kimelman-Bleich, N., Pelled, G., Zilberman, Y., Gazit, D. and Gazit, Z. (2008) Ultrasound-based nonviral gene delivery induces bone formation in vivo. Gene Therapy, 15, 257-266. doi:10.1038/sj.gt.3303070
[132] Bergeron, E., Senta, H., Mailloux, A., Park, H., Lord, E. and Faucheux, N. (2009) Murine preosteoblast differenttiation induced by a peptide derived from bone morphogenetic proteins-9. Tissue Engineering Part A, 15, 3341-3349. doi:10.1089/ten.tea.2009.0189
[133] Lee, J.Y., Peng, H., Usas, A., Musgrave, D., Cummins, J., Pelinkovic, D., Jankowski, R., Ziran, B., Robbins, P. and Huard, J. (2002) Enhancement of bone healing based on ex vivo gene therapy using human muscle-derived cells expressing bone morphogenetic protein 2. Human Gene Therapy, 13, 1201-1211. doi:10.1089/104303402320138989
[134] 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.
[135] Kimelman-Bleich, N., Pelled, G., Zilberman, Y., Kallai, I., Mizrahi, O., Tawackoli, W., Gazit, Z. and Gazit, D. (2011) Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair. Molecular Therapy, 19, 53-59. doi:10.1038/mt.2010.190
[136] Li, X., Chen. L., Ke, Z.-Y., Yin, L.-J. and Deng, Z.-L. (2012) BMP9-induced osteogenic differentiation and bone formation of muscle-derived stem cells. Journal of Biomedicine and Biotechnology, 2012, 1.
[137] Brown, M.A., Zhao, Q., Baker, K.A., Naik, C., Chen, C., Pukac, L., Singh, M., Tsareva, T., Parice, Y., Mahoney, A., Roschke, V., Sanyal, I. and Choe, S. (2005) Crystal structure of BMP-9 and functional interactions with pro-region and receptors. The Journal of Biological Chemistry, 280, 25111-25118. doi:10.1074/jbc.M503328200
[138] Canalis, E., Economides, A.N. and Gazzerro, E. (2003) Bone morphogenetic proteins, their antagonists, and the skeleton. Endocrine Reviews, 24, 218-235. doi:10.1210/er.2002-0023
[139] Hill, J.J., Qiu, Y., Hewick, R.M. and Wolfman, N.M. (2003) Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1: A novel protein with protease inhibitor and follistatin domains. Molecular Endocrinology, 17, 1144-1154. doi:10.1210/me.2002-0366
[140] Li, J.Z., Li, H., Sasaki, T., Holman, D., Beres, B., Dumont, R.J., Pittman, D.D., Hankins, G.R. and Helm, G.A. (2003) Osteogenic potential of five different recombinant human bone morphogenetic protein adenoviral vectors in the rat. Gene Therapy, 10, 1735-1743. doi:10.1038/sj.gt.3302075
[141] Sieber, C., Kopf, J., Hiepen, C. and Knaus, P. (2009) Recent advances in BMP receptor signaling. Cytokine & Growth Factor Reviews, 20, 343-355. doi:10.1016/j.cytogfr.2009.10.007
[142] Zhou, L., An, N., Jiang, W., Haydon, R., Cheng, H., Zhou, Q., Breyer, B., Feng, T. and He, T.C. (2002) Fluorescence-based functional assay for Wnt/beta-catenin signaling activity. Biotechniques, 33, 1126-1128, 1130, 1132 passim.
[143] Massague, J. (1998) TGF-beta signal transduction. Annual Review of Biochemistry, 67, 753-791. doi:10.1146/annurev.biochem.67.1.753
[144] Yamashita, H., Ten Dijke, P., Heldin, C.H. and Miyazono, K. (1996) Bone morphogenetic protein receptors. Bone, 19, 569-574. doi:10.1016/S8756-3282(96)00259-1
[145] Yamashita, H. and Miyazono, K. (1999) Bone morphogenetic protein (BMP) receptors and signal transduction. Nihon Rinsho, 57, 220-226.
[146] 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 VEGF-stimulated angiogenesis. Journal of Cell Science, 120, 964-972. doi:10.1242/jcs.002949
[147] Shao, E.S., Lin, L., Yao, Y. and Bostrom, K.I. (2009) Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood, 114, 2197-2206. doi:10.1182/blood-2009-01-199166
[148] Upton, P.D., Davies, R.J., Trembath, R.C. and Morrell, N.W. (2009) Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells. The Journal of Biological Chemistry, 284, 15794-15804. doi:10.1074/jbc.M109.002881
[149] Massague, J., Seoane, J. and Wotton, D. (2005) Smad transcription factors. Genes & Development, 19, 2783-2810. doi:10.1101/gad.1350705
[150] Nohe, A., Keating, E., Knaus, P. and Petersen, N.O. (2004) Signal transduction of bone morphogenetic protein receptors. Cellular Signalling, 16, 291-299. doi:10.1016/j.cellsig.2003.08.011
[151] Heldin, C.H., Miyazono, K. and ten Dijke, P. (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature, 390, 465-471.
[152] Wrana, J.L. (2000) Regulation of Smad activity. Cell, 100, 189-192. doi:10.1016/S0092-8674(00)81556-1
[153] Derynck, R., Zhang, Y. and Feng, X.H. (1998) Smads: transcriptional activators of TGF-beta responses. Cell, 95, 737-740. doi:10.1016/S0092-8674(00)81696-7
[154] Itoh, S., Itoh, F., Goumans, M.J. and Ten Dijke, P. (2000) Signaling of transforming growth factor-beta family members through Smad proteins. European Journal of Biochemistry, 267, 6954-6967. doi:10.1046/j.1432-1327.2000.01828.x
[155] Miyazono, K., ten Dijke, P. and Heldin, C.H. (2000) TGF-beta signaling by Smad proteins. Advances in Immunology, 75, 115-157. doi:10.1016/S0065-2776(00)75003-6
[156] Ten Dijke, P., Goumans, M.J., Itoh, F. and Itoh, S. (2002) Regulation of cell proliferation by Smad proteins. Journal of Cellular Physiology, 191, 1-16. doi:10.1002/jcp.10066
[157] 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. doi:10.1016/j.cytogfr.2005.01.009
[158] Xu, D.J., Zhao, Y.-Z., Wang, J., He, J.W., Weng, Y.G. and Luo, J.Y. (2011) Smads, p38 and ERK1/2 are involved in BMP9-induced osteogenic differentiation of C3H10T1/2 mesenchymal stem cells. BMB Reports, 45, 247-252.
[159] Kreider, B.L., Benezra, R., Rovera, G. and Kadesch, T. (1992) Inhibition of myeloid differentiation by the helixloop-helix protein Id. Science, 255, 1700-1702. doi:10.1126/science.1372755
[160] Norton, J.D. (2000) ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. Journal of Cell Science, 113, 3897-3905.
[161] Ruzinova, M.B. and Benezra, R. (2003) Id proteins in development, cell cycle and cancer. Trends in Cell Biology, 13, 410-418. doi:10.1016/S0962-8924(03)00147-8
[162] Blom, I.E., Goldschmeding, R. and Leask, A. (2002) Gene regulation of connective tissue growth factor: New targets for antifibrotic therapy? Matrix Biology, 21, 473-482. doi:10.1016/S0945-053X(02)00055-0
[163] Brigstock, D.R. (2003) The CCN family: A new stimulus package. Journal of Endocrinology, 178, 169-175. doi:10.1677/joe.0.1780169
[164] Brigstock, D.R., Goldschmeding, R., Katsube, K.I., Lam, S.C., Lau, L.F., Lyons, K., Naus, C., Perbal, B., Riser, B., Takigawa, M. and Yeger, H. (2003) Proposal for a unified CCN nomenclature. Molecular Pathology, 56, 127-128. doi:10.1136/mp.56.2.127
[165] Lau, L.F. and Lam, S.C. (1999) The CCN family of angiogenic regulators: The integrin connection. Experimental Cell Research, 248, 44-57. doi:10.1006/excr.1999.4456
[166] Moussad, E.E. and Brigstock, D.R. (2000) Connective tissue growth factor: What’s in a name? Molecular Genetics and Metabolism, 71, 276-292. doi:10.1006/mgme.2000.3059
[167] Planque, N. and Perbal, B. (2003) A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis. Cancer Cell International, 3, 15. doi:10.1186/1475-2867-3-15
[168] Ivkovic, S., Yoon, B.S., Popoff, S.N., Safadi, F.F., Libuda, D.E., Stephenson, R.C., Daluiski, A. and Lyons, K.M. (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development and Disease, 130, 2779-2791. doi:10.1242/dev.00505
[169] Sharff, K.A., Song, W.X., Luo, X., Tang, N., Luo, J., Chen, J., Bi, Y., He, B.C., Huang, J., Li, X., Jiang, W., Zhu, G.H., Su, Y., He, Y., Shen, J., Wang, Y., Chen, L., Zuo, G.W., Liu, B., Pan, X., Reid, R.R., Luu, H.H., Haydon, R.C. and He, T.C. (2009) Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. The Journal of Biological Chemistry, 284, 649-659. doi:10.1074/jbc.M806389200
[170] Massague, J. and Chen, Y.G. (2000) Controlling TGF-beta signaling. Genes & Development, 14, 627-644.
[171] Massague, J. and Wotton, D. (2000) Transcriptional control by the TGF-beta/Smad signaling system. The EMBO Journal, 19, 1745-1754. doi:10.1093/emboj/19.8.1745
[172] Siegel, P.M. and Massague, J. (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nature Reviews. Cancer, 3, 807-821.
[173] Siegel, P.M., Shu, W., Cardiff, R.D., Muller, W.J. and Massague, J. (2003) Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proceedings of the National Academy of Sciences of the United States of America, 100, 8430-8435. doi:10.1073/pnas.0932636100
[174] Alliston, T., Choy, L., Ducy, P., Karsenty, G. and Derynck, R. (2001) TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. The EMBO Journal, 20, 2254-2272. doi:10.1093/emboj/20.9.2254
[175] Li, R.D., Deng, Z.L., Hu, N., Liang, X., Liu, B., Luo, J., Chen, L., Yin, L., Luo, X., Shui, W., He, T.C. and Huang, W. (2012) Biphasic effects of TGFbeta1 on BMP9-induced osteogenic differentiation of mesenchymal stem cells. BMB Reports, 45, 509-514.
[176] Maeda, S., Hayashi, M., Komiya, S., Imamura, T. and Miyazono, K. (2004) Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells. The EMBO Journal, 23, 552-563. doi:10.1038/sj.emboj.7600067
[177] Huang, E., Zhu, G., Jiang, W., Yang, K., Gao, Y., Luo, Q., Gao, J.L., Kim, S.H., Liu, X., Li, M., Shi, Q., Hu, N., Wang, L., Liu, H., Cui, J., Zhang, W., Li, R., Chen, X., Kong, Y.H., Zhang, J., Wang, J., Shen, J., Bi, Y., Statz, J., He, B.C., Luo, J., Wang, H., Xiong, F., Luu, H.H., Haydon, R.C., Yang, L. and He, T.C. (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. doi:10.1002/jbmr.1622
[178] Blair, J.C. and Savage, M.O. (2002) The GH-IGF-I axis in children with idiopathic short stature. Trends in Endocrinology & Metabolism, 13, 325-330. doi:10.1016/S1043-2760(02)00631-8
[179] Brooks, A.J. and Waters, M.J. (2010) The growth hormone receptor: Mechanism of activation and clinical implications. Nature Reviews. Endocrinology, 6, 515-525.
[180] Hull, K.L. and Harvey, S. (2000) Growth hormone: Roles in male reproduction. Endocrine, 13, 243-250. doi:10.1385/ENDO:13:3:243
[181] Hull, K.L. and Harvey, S. (2000) Growth hormone: A reproductive endocrine-paracrine regulator? Reviews of Reproduction, 5, 175-182. doi:10.1530/ror.0.0050175
[182] Park, P. and Cohen, P. (2005) Insulin-like growth factor I (IGF-I) measurements in growth hormone (GH) therapy of idiopathic short stature (ISS). Growth Hormone & IGF Research, 15, S13-S20.
[183] Tanaka, H. (1998) Growth hormone and bone diseases. Endocrine Journal, 45, S47-S52. doi:10.1507/endocrj.45.Suppl_S47
[184] Thomas, M.J. (1998) The molecular basis of growth hormone action. Growth Hormone & IGF Research, 8, 3-11. doi:10.1016/S1096-6374(98)80316-X
[185] Randhawa, R. and Cohen, P. (2005) The role of the insulin-like growth factor system in prenatal growth. Molecular Genetics and Metabolism, 86, 84-90. doi:10.1016/j.ymgme.2005.07.028
[186] O’Dell, S.D. and Day, I.N. (1998) Insulin-like growth factor II (IGF-II). The International Journal of Biochemistry & Cell Biology, 30, 767-771. doi:10.1016/S1357-2725(98)00048-X
[187] Bergwitz, C., Wendlandt, T., Kispert, A. and Brabant, G. (2001) Wnts differentially regulate colony growth and differentiation of chondrogenic rat calvaria cells. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1538, 129-140. doi:10.1016/S0167-4889(00)00123-3
[188] Cadigan, K.M. and Nusse, R. (1997) Wnt signaling: A common theme in animal development. Genes & Development, 11, 3286-3305. doi:10.1101/gad.11.24.3286
[189] Fischer, L., Boland, G. and Tuan, R.S. (2002) Wnt signaling during BMP-2 stimulation of mesenchymal chondrogenesis. Journal of Cellular Physiology, 84, 816-831. doi:10.1002/jcb.10091
[190] Glass 2nd., D.A. and Karsenty, G. (2006) Molecular bases of the regulation of bone remodeling by the canonical Wnt signaling pathway. Current Topics in Developmental Biology, 73, 43-84. doi:10.1016/S0070-2153(05)73002-7
[191] Glass 2nd., D.A. and Karsenty, G. (2007) In vivo analysis of Wnt signaling in bone. Endocrinology, 148, 2630-2634. doi:10.1210/en.2006-1372
[192] Karsenty, G. and Wagner, E.F. (2002) Reaching a genetic and molecular understanding of skeletal development. Developmental Cell, 2, 389-406. doi:10.1016/S1534-5807(02)00157-0
[193] Wang, J. and Wynshaw-Boris, A. (2004) The canonical Wnt pathway in early mammalian embryogenesis and stem cell maintenance/differentiation. Current Opinion in Genetics & Development, 14, 533-539. doi:10.1016/j.gde.2004.07.013
[194] Tang, N., Song, W.X., Luo, J., Luo, X., Chen, J., Sharff, K.A., Bi, Y., He, B.C., Huang, J.Y., Zhu, G.H., Su, Y.X., Jiang, W., Tang, M., He, Y., Wang, Y., Chen, L., Zuo, G.W., Shen, J., Pan, X., Reid, R.R., Luu, H.H., Haydon, R.C. and He, T.C. (2009) BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signalling. Journal of Cellular and Molecular Medicine, 13, 2448-2464. doi:10.1111/j.1582-4934.2008.00569.x
[195] Gong, Y., Slee, R.B., Fukai, N., Rawadi, G., Roman-Roman, S., Reginato, A.M., Wang, H., Cundy, T., Glorieux, F.H., Lev, D., Zacharin, M., Oexle, K., Marcelino, J., Suwairi, W., Heeger, S., Sabatakos, G., Apte, S., Adkins, W.N., Allgrove, J., Arslan-Kirchner, M., Batch, J.A., Beighton, P., Black, G.C., Boles, R.G., Boon, L.M., Borrone, C., Brunner, H.G., Carle, G.F., Dallapiccola, B., De Paepe, A., Floege, B., Halfhide, M.L., Hall, B., Hennekam, R.C., Hirose, T., Jans, A., Juppner, H., Kim, C.A., Keppler-Noreuil, K., Kohlschuetter, A., LaCombe, D., Lambert, M., Lemyre, E., Letteboer, T., Peltonen, L., Ramesar, R.S., Romanengo, M., Somer, H., Steichen-Gersdorf, E., Steinmann, B., Sullivan, B., Superti-Furga, A., Swoboda, W., van den Boogaard, M.J., Van Hul, W., Vikkula, M., Votruba, M., Zabel, B., Garcia, T., Baron, R., Olsen, B.R. and Warman, M.L. (2001) LDL receptorrelated protein 5 (LRP5) affects bone accrual and eye development. Cell, 107, 513-523. doi:10.1016/S0092-8674(01)00571-2
[196] Celil, A.B. and Campbell, P.G. (2005) BMP-2 and insulin-like growth factor-I mediate osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. The Journal of Biological Chemistry, 280, 31353-31359. doi:10.1074/jbc.M503845200
[197] Chang, S.F., Chang, T.K., Peng, H.H., Yeh, Y.T., Lee, D.Y., Yeh, C.R., Zhou, J., Cheng, C.K., Chang, C.A. and Chiu, J.J. (2009) BMP-4 induction of arrest and differenttiation of osteoblast-like cells via p21CIP1 and p27KIP1 regulation. Molecular Endocrinology, 23, 1827-1838. doi:10.1210/me.2009-0143
[198] Gallea, S., Lallemand, F., Atfi, A., Rawadi, G., Ramez, V., Spinella-Jaegle, S., Kawai, S., Faucheu, C., Huet, L., Baron, R. and Roman-Roman, S. (2001) Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. Bone, 28, 491-498. doi:10.1016/S8756-3282(01)00415-X
[199] Noth, U., Tuli, R., Seghatoleslami, R., Howard, M., Shah, A., Hall, D.J., Hickok, N.J. and Tuan, R.S. (2003) Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts. Experimental Cell Research, 291, 201-211. doi:10.1016/S0014-4827(03)00386-0
[200] Miyazono, K., Kamiya, Y. and Morikawa, M. (2010) Bone morphogenetic protein receptors and signal transduction. The Journal of Biochemistry, 147, 35-51. doi:10.1093/jb/mvp148
[201] Verheyen, E.M. (2007) Opposing effects of Wnt and MAPK on BMP/Smad signal duration. Developmental Cell, 13, 755-756. doi:10.1016/j.devcel.2007.11.006
[202] Majmundar, A.J., Wong, W.J. and Simon, M.C. (2010) Hypoxia-inducible factors and the response to hypoxic stress. Molecular Cell, 40, 294-309. doi:10.1016/j.molcel.2010.09.022
[203] Giaginis, C., Tsantili-Kakoulidou, A. and Theocharis, S. (2007) Peroxisome proliferator-activated receptors (PPARs) in the control of bone metabolism. Fundamental & Clinical Pharmacology, 21, 231-244. doi:10.1111/j.1472-8206.2007.00486.x
[204] Muruganandan, S., Roman, A.A. and Sinal, C.J. (2009) Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: Cross talk with the osteoblastogenic program. Cellular and Molecular Life Sciences, 66, 236-253. doi:10.1007/s00018-008-8429-z
[205] Chawla, A., Repa, J.J., Evans, R.M. and Mangelsdorf, D.J. (2001) Nuclear receptors and lipid physiology: Opening the X-files. Science, 294, 1866-1870. doi:10.1126/science.294.5548.1866
[206] Mark, M., Ghyselinck, N.B. and Chambon, P. (2006) Function of retinoid nuclear receptors: Lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annual Review of Pharmacology and Toxicology, 46, 451-480. doi:10.1146/annurev.pharmtox.46.120604.141156
[207] Chen, L., Jiang, W., Huang, J., He, B.C., Zuo, G.W., Zhang, W., Luo, Q., Shi, Q., Zhang, B.Q., Wagner, E.R., Luo, J., Tang, M., Wietholt, C., Luo, X., Bi, Y., Su, Y., Liu, B., Kim, S.H., He, C.J., Hu, Y., Shen, J., Rastegar, F., Huang, E., Gao, Y., Gao, J.L., Zhou, J.Z., Reid, R.R., Luu, H.H., Haydon, R.C., He, T.C. and Deng, Z.L. (2010) Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation. Journal of Bone and Mineral Research, 25, 2447-2459. doi:10.1002/jbmr.133
[208] Zhao, Y., Song, T., Wang, W., Wang, J., He, J., Wu, N., Tang, M., He, B. and Luo, J. (2012) P38 and ERK1/2 MAPKs act in opposition to regulate BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. PLoS One, 7, e43383. doi:10.1371/journal.pone.0043383
[209] Hu, N., Jiang, D., Huang, E., Liu X., Li, R.D., Liang, X., Stephanie, H. and Kim, X.C., Gao, J.-L., Zhang, H.Y. and Zhang, W.W. (2013) BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells. Journal of Cell Science, 126, 532-541.
[210] Zhang, W., Deng, Z.L., Chen, L., Zuo, G.W., Luo, Q., Shi, Q., Zhang, B.Q., Wagner, E.R., Rastegar, F., Kim, S.H., Jiang, W., Shen, J., Huang, E., Gao, Y., Gao, J.L., Zhou, J.Z., Luo, J., Huang, J., Luo, X., Bi, Y., Su, Y., Yang, K., Liu, H., Luu, H.H., Haydon, R.C., He, T.C. and He, B.C. (2010) Retinoic acids potentiate BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. PLoS One, 5, e11917. doi:10.1371/journal.pone.0011917
[211] Castonguay, R., Werner, E.D., Matthews, R.G., Presman, E., Mulivor, A.W., Solban, N., Sako, D., Pearsall, R.S, Underwood, K.W., Seehra, J., Kumar, R. and Grinberg, A.V. (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. doi:10.1074/jbc.M111.260133
[212] 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. Internation Journal of Oncology, 41, 1809-1819.
[213] 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. doi:10.1158/1541-7786.MCR-08-0171
[214] van Meeteren, L.A., Thorikay, M., Bergqvist, S., Pardali, E., Stampino, C.G., Hu-Lowe, D., Goumans, M.J. and ten Dijke, P. (2012) Anti-human activin receptor-like kinase 1 (ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and interferes with endothelial cell sprouting. The Journal of Biological Chemistry, 287, 18551-18561. doi:10.1074/jbc.M111.338103
[215] Ricard, N., Ciais, D., Levet, S., Subileau, M., Mallet, C., Zimmers, T.A., Lee, S.J., Bidart, M., Feige, J.J. and Bailly, S. (2012) BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood, 119, 6162-6171. doi:10.1182/blood-2012-01-407593
[216] 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. doi:10.1242/jcs.061556
[217] 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. doi:10.1161/CIRCRESAHA.107.165530
[218] Park, J.E., Shao, D., Upton, P.D., Desouza, P., Adcock, I.M., Davies, R.J., Morrell, N.W., Griffiths, M.J. and Wort, S.J. (2012) BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. PLoS One, 7, e30075. doi:10.1371/journal.pone.0030075
[219] Yao, Y., Jumabay, M., Ly, A., Radparvar, M., Wang, A.H., Abdmaulen, R. and Bostrom, K.I. (2012) Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium. Blood, 119, 5037-5047. doi:10.1182/blood-2011-10-385906
[220] 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. doi:10.1073/pnas.0502097102
[221] 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. doi:10.1371/journal.pone.0021166
[222] Schnitzler, A.C., Lopez-Coviella, I. and Blusztajn, J.K. (2008) Differential modulation of nerve growth factor receptor (p75) and cholinergic gene expression in purified p75-expressing and non-expressing basal forebrain neurons by BMP9. Brain Research, 1246, 19-28. doi:10.1016/j.brainres.2008.09.085
[223] Schnitzler, A.C., Mellott, T.J., Lopez-Coviella, I., Tallini, Y.N., Kotlikoff, M.I., Follettie, M.T. and Blusztajn, J.K. (2010) BMP9 (bone morphogenetic protein 9) induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons. Journal of Neuroscience, 30, 8221-8228. doi:10.1523/JNEUROSCI.5611-09.2010
[224] 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. doi:10.1210/en.2008-0655
[225] 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. doi:10.12659/MSM.882108
[226] 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. doi:10.1080/0897719031000148822
[227] 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. doi:10.1002/jcp.10025

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