Networks and hubs for the transcriptional control of osteoblastogenesis

Reviews in Endocrine and Metabolic Disorders

Volumn 7, Issue 1-2, 2006, Pages 1-16

  Lian, Jane B ^a   Stein, Gary S ^a   Javed, Amjad ^b   Van Wijnen, Andre J ^a   Stein, Janet L ^a   Montecino, Martin ^c   Hassan, Mohammad Q ^a   Gaur, Tripti ^a   Lengner, Christopher J ^a   Young, Daniel W ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^c UNIVERSITY OF CONCEPCIÓN   (Chile)

Author keywords

BMP and Wnt osteogenic signaling; Cell fate determinant; Homeodomain proteins; Skeletal development; Subnuclear transcription domains

Indexed keywords

CYTOKINE; GROWTH FACTOR; HORMONE; TRANSCRIPTION FACTOR RUNX2;

BONE CELL; BONE DEVELOPMENT; CELL DIFFERENTIATION; GENE ACTIVATION; GENE EXPRESSION; GENE TARGETING; GENETIC TRANSCRIPTION; HUMAN; MOLECULAR DYNAMICS; NONHUMAN; OSSIFICATION; OSTEOBLAST; PHENOTYPE; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; BONE MORPHOGENETIC PROTEINS; BONE NEOPLASMS; CARCINOMA; CELL DIFFERENTIATION; CORE BINDING FACTOR ALPHA 1 SUBUNIT; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENE REGULATORY NETWORKS; HUMANS; MODELS, BIOLOGICAL; NEOPLASM METASTASIS; OSTEOBLASTS; OSTEOGENESIS; SIGNAL TRANSDUCTION; SMAD PROTEINS; WNT PROTEINS;

EID: 33845987376     PISSN: 13899155     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11154-006-9001-5     Document Type: Review

References (184)

1. Rosen CJ. The cellular and clinical parameters of anabolic therapy for osteoporosis. Crit Rev Eukaryot Gene Expr 2003;13:25-38.
2. Tashjian Jr AH, Gagel RF. Teriparatide [human PTH(1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res 2006;21:354-65.
3. Bilezikian JP, Rubin MR. Combination/sequential therapies for anabolic and antiresorptive skeletal agents for osteoporosis. Curr Osteoporos Rep 2006;4:5-13.
4. Otto F, Kanegane H, Mundlos S. Mutations in the RUNX2 gene in patients with cleidocranial dysplasia. Hum Mutat 2002;19:209-16.
5. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997;89:755-64.
6. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 1997;89:773-9.
7. Komori T. Requisite roles of Runx2 and Cbfb in skeletal development. J Bone Miner Metab 2003;21:193-7.
8. Choi KY, Lee SW, Park MH, Bae YC, Shin HI, Nam S, et al. Spatio-temporal expression patterns of Runx2 isoforms in early skeletogenesis. Exp Mol Med 2002;34:426-33.
9. Ornitz DM. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 2005;16:205-13.
10. Provot S, Schipani E. Molecular mechanisms of endochondral bone development. Biochem Biophys Res Commun 2005;328:658-65.
11. Romero-Prado M, Blazquez C, Rodriguez-Navas C, Munoz J, Guerrero I, gado-Baeza E, et al. Functional characterization of human mesenchymal stem cells that maintain osteochondral fates. J Cell Biochem 2006; in press.
12. Lengner CJ, Drissi H, Choi J-Y, van Wijnen AJ, Stein JL, Stein GS, et al. Activation of the bone related Runx2/Cbfa1 promoter in mesenchymal condensations and developing chondrocytes of the axial skeleton. Mech Dev 2002;114:167-70.
13. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997;89:747-54.
14. Lian JB, Balint E, Javed A, Drissi H, Vitti R, Quinlan EJ, et al. Runx1/AML1 hematopoietic transcription factor contributes to skeletal development in vivo. J Cell Physiol 2003;196:301-11.
15. Wang Y, Belflower RM, Dong YF, Schwarz EM, O'Keefe RJ, Drissi H. Runx1/AML1/Cbfa2 mediates onset of mesenchymal cell differentiation toward chondrogenesis. J Bone Miner Res 2005;20:1624-36.
16. Lengner CJ, Steinman HA, Gagnon J, Kream BE, Stein GS, Lian JB, et al. Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. J Cell Biol 2006; 172:909-21.
17. Smith N, Dong Y, Pratap J, Lian JB, Kingsley P, van Wijnen AJ, et al. Overlapping expression of Runx1(Cbfa2) and Runx2 (Cbfa1) transcription factors supports cooperative induction of skeletal development. J Cell Pysiol 2005;203:133-43.
18. Drissi H, Luc Q, Shakoori R, Chuva de Sousa Lopes S, Choi J-Y, Terry A, et al. Transcriptional autoregulation of the bone related CBFA1/RUNX2 gene. J Cell Physiol 2000;184:341-50.
19. 3. J Cell Biochem 2006; in press.
20. Zaidi SK, Young DW, Choi JY, Pratap J, Javed A, Montecino M, et al. Intranuclear trafficking: organization and assembly of regulatory machinery for combinatorial biological control. J Biol Chem 2004;279:43363-6.
21. Pratap J, Javed A, Languino LR, van Wijnen AJ, Stein JL, Stein GS, et al. The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. Mol Cell Biol 2005;25:8581-91.
22. Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY, et al. The bone-specific expression of RUNX2 oscillates during the cell cycle to support a G1 related anti-proliferative function in osteoblasts. J Biol Chem 2005;280:20274-85.
23. Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen AJ, Lian JB, et al. Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Mol Cell Biol 2002;22:7982-92.
24. Thomas DM, Johnson SA, Sims NA, Trivett MK, Slavin JL, Rubin BP, et al. Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. J Cell Biol 2004;167:925-34.
25. Wang X, Kua HY, Hu Y, Guo K, Zeng Q, Wu Q, et al. p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling. J Cell Biol 2006;172:115-25.
26. Zambetti GP, Horwitz EM, Schipani E. Skeletons in the p53 tumor suppressor closet: genetic evidence that p53 blocks bone differentiation and development. J Cell Biol 2006;172:795-7.
27. Young DW, Galindo M, Yang X, Underwood J, Pratap J, Stein JL, et al. The RUNX2 transcription factor regulates ribosomal RNA gene expression for osteoblast growth and differentiation. J Bone Miner Res (Abstract) 2005;20:S15.
28. Lengner CJ, Hassan MQ, Serra RW, Lepper C, van Wijnen AJ, Stein JL, et al. Nkx3.2 mediated repression of RUNX2 promotes chondrogenic differentiation. J Biol Chem 2005;280:15872-9.
29. Provot S, Kempf H, Murtaugh LC, Chung UI, Kim DW, Chyung J, et al. Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation. Development 2006;133:651-62.
30. Murtaugh LC, Zeng L, Chyung JH, Lassar AB. The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP-dependent axial chondrogenesis. Dev Cell 2001;1:411-22.
31. Eames BF, Sharpe PT, Helms JA. Hierarchy revealed in the specification of three skeletal fates by Sox9 and Runx2. Dev Biol 2004;274:188-200.
32. Guo J, Chung UI, Yang D, Karsenty G, Bringhurst FR, Kronenberg HM. PTH/PTHrP receptor delays chondrocyte hypertrophy via both Runx2-dependent and -independent pathways. Dev Biol 2006;292:116-28.
33. Iwamoto M, Kitagaki J, Tamamura Y, Gentili C, Koyama E, Enomoto H, et al. Runx2 expression and action in chondrocytes are regulated by retinoid signaling and parathyroid hormone-related peptide (PTHrP). Osteoarthritis Cartilage 2003;11:6-15.
34. Li TF, Dong Y, Ionescu AM, Rosier RN, Zuscik MJ, Schwarz EM, et al. Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway. Exp Cell Res 2004;299:128-36.
35. Zelzer E, Glotzer DJ, Hartmann C, Thomas D, Fukai N, Soker S, et al. Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mech Dev 2001;106:97-106.
36. ten Dijke P, Fu J, Schaap P, Roelen BA. Signal transduction of bone morphogenetic proteins in osteoblast differentiation. J Bone Joint Surg Am 2003;85-A Suppl 3:34-8.
37. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004;22:233-41.
38. Mishina Y, Starbuck MW, Gentile MA, Fukuda T, Kasparcova V, Seedor JG, et al. Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J Biol Chem 2004;279:27560-6.
39. Noth U, Tuli R, Seghatoleslami R, Howard M, Shah A, Hall DJ, et al. Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts. Exp Cell Res 2003;291:201-11.
40. Lee KS, Hong SH, Bae SC. Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. Oncogene 2002;21:7156-63.
41. Guicheux J, Lemonnier J, Ghayor C, Suzuki A, Palmer G, Caverzasio J. Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. J Bone Miner Res 2003;18:2060-8.
42. Ghosh-Choudhury N, Woodruff K, Qi W, Celeste A, Abboud SL, Ghosh CG. Bone morphogenetic protein-2 blocks MDA MB 231 human breast cancer cell proliferation by inhibiting cyclin-dependent kinase-mediated retinoblastoma protein phosphorylation. Biochem Biophys Res Commun 2000;272:705-11.
43. Celil AB, Campbell PG. 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. J Biol Chem 2005;280:31353-9.
44. Hay E, Lemonnier J, Fromigue O, Marie PJ. Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway. J Biol Chem 2001;276:29028-36.
45. Lai CF, Cheng SL. Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-beta in normal human osteoblastic cells. J Biol Chem 2002;277:15514-22.
46. Gallea S, Lallemand F, Atfi A, Rawadi G, Ramez V, Spinella-Jaegle S, et al. Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. Bone 2001;28:491-8.
47. Balint E, Lapointe D, Drissi H, van der Meijden C, Young DW, van Wijnen AJ, et al. Phenotype discovery by gene expression profiling: mapping of biological processes linked to BMP-2-mediated osteoblast differentiation. J Cell Biochem 2003;89:401-26.
48. Harris SE, Guo D, Harris MA, Krishnaswamy A, Lichtler A. Transcriptional regulation of BMP-2 activated genes in osteoblasts using gene expression microarray analysis: role of Dlx2 and Dlx5 transcription factors. Front Biosci 2003;8:s1249-65.
49. Bendall AJ, Abate-Shen C. Roles for Msx and Dlx homeoproteins in vertebrate development. Gene 2000;247:17-31.
50. Depew MJ, Lufkin T, Rubenstein JL. Specification of jaw subdivisions by Dlx genes. Science 2002;298:381-5.
51. Dodig M, Tadic T, Kronenberg MS, Dacic S, Liu YH, Maxson R, et al. Ectopic Msx2 overexpression inhibits and Msx2 antisense stimulates calvarial osteoblast differentiation. Dev Biol 1999;209: 298-307.
52. Lee MH, Kwon TG, Park HS, Wozney JM, Ryoo HM. BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Biochem Biophys Res Commun 2003;309:689-94.
53. Lee MH, Kim YJ, Kim HJ, Park HD, Kang AR, Kyung HM, et al. BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. J Biol Chem 2003;278:34387-94.
54. Hassan MQ, Javed A, Morasso MI, Karlin J, Montecino M, van Wijnen AJ, et al. Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene. Mol Cell Biol 2004;24:9248-61.
55. Ferrari D, Harrington A, Dealy CN, Kosher RA. Dlx-5 in limb initiation in the chick embryo. Dev Dyn 1999;216:10-5.
56. Bidder M, Latifi T, Towler DA. Reciprocal temporospatial patterns of Msx2 and Osteocalcin gene expression during murine odontogenesis. J Bone Miner Res 1998;13:609-19.
57. Depew MJ, Simpson CA, Morasso M, Rubenstein JL. Reassessing the Dlx code: the genetic regulation of branchial arch skeletal pattern and development. J Anat 2005;207:501-61.
58. Holleville N, Quilhac A, Bontoux M, Monsoro-Burq AH. BMP signals regulate Dlx5 during early avian skull development. Dev Biol 2003;257:177-89.
59. Ichida F, Nishimura R, Hata K, Matsubara T, Ikeda F, Hisada K, et al. Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. J Biol Chem 2004;279:34015-22.
60. Yoshizawa T, Takizawa F, Iizawa F, Ishibashi O, Kawashima H, Matsuda A, et al. Homeobox protein MSX2 acts as a molecular defense mechanism for preventing ossification in ligament fibroblasts. Mol Cell Biol 2004;24:3460-72.
61. Cheng SL, Shao JS, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J Biol Chem 2003;278:45969-77.
62. Tadic T, Dodig M, Erceg I, Marijanovic I, Mina M, Kalajzic Z, et al. Overexpression of Dlx5 in chicken calvarial cells accelerates osteoblastic differentiation. J Bone Miner Res 2002;17:1008-14.
63. Lee MH, Kim YJ, Yoon WJ, Kim JI, Kim BG, Hwang YS, et al. Dlx5 specifically regulates Runx2-II expression by binding to homeodomain response elements in the Runx2 distal promoter. J Biol Chem 2005;280:35579-87.
64. Shirakabe K, Terasawa K, Miyama K, Shibuya H, Nishida E. Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5. Genes Cells 2001;6:851-6.
65. Hassan MQ, Tare R, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Hoxa10: a BMP2-responsive gene activates Runx2 and regulates osteogenesis. J Bone Miner Res (Abstract) 2005;20:S5.
66. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002;108:17-29.
67. Nishio Y, Dong Y, Paris M, O'Keefe RJ, Schwarz EM, Drissi H. Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 2006; in press.
68. Kim YJ, Kim HN, Park EK, Lee BH, Ryoo HM, Kim SY, et al. The bone-related Zn finger transcription factor Osterix promotes proliferation of mesenchymal cells. Gene 2006;366:145-51.
69. Pratap J, Galindo M, Zaidi SK, Vradii D, Bhat BM, Robinson JA, et al. Cell growth regulatory role of Runx2 during proliferative expansion of pre-osteoblasts. Cancer Res 2003;63:5357-62.
70. Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 2005;202:1261-9.
71. Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K, et al. NFAT and Osterix cooperatively regulate bone formation. Nat Med 2005;11:880-5.
72. Sowa H, Kaji H, Canaff L, Hendy GN, Tsukamoto T, Yamaguchi T, et al. Inactivation of menin, the product of the multiple endocrine neoplasia type 1 gene, inhibits the commitment of multipotential mesenchymal stem cells into the osteoblast lineage. J Biol Chem 2003;278:21058-69.
73. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, et al. A twist code determines the onset of osteoblast differentiation. Dev Cell 2004;6:423-35.
74. Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, et al. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev 2003;17:1979-91.
75. Pockwinse SM, Rajgopal A, Young DW, Mujeeb KA, Nickerson J, Javed A, et al. Microtubule-dependent nuclear-cytoplasmic shuttling of Runx2. J Cell Physiol 2006;206:354-62.
76. Castilla LH, Wijmenga C, Wang Q, Stacy T, Speck NA, Eckhaus M, et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell 1996;87:687-96.
77. Miller J, Horner A, Stacy T, Lowrey C, Lian JB, Stein G, et al. The core-binding factor beta subunit is required for bone formation and hematopoietic maturation. Nat Genet 2002;32: 645-9.
78. Yoshida CA, Furuichi T, Fujita T, Fukuyama R, Kanatani N, Kobayashi S, et al. Core-binding factor beta interacts with Runx2 and is required for skeletal development. Nat Genet 2002;32:633-8.
79. Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, et al. Cbfbeta interacts with Runx2 and has a critical role in bone development. Nat Genet 2002;32:639-44.
80. Kahler RA, Westendorf JJ. Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter. J Biol Chem 2003;278:11937-44.
81. Khan E, bu-Amer Y. Activation of peroxisome proliferator-activated receptor-gamma inhibits differentiation of preosteoblasts. J Lab Clin Med 2003;142:29-34.
82. Xiao G, Jiang D, Ge C, Zhao Z, Lai Y, Boules H, et al. Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem 2005;280:30689-96.
83. Gutierrez S, Javed A, Tennant D, van Rees M, Montecino M, Stein GS, et al. CCAAT/enhancer-binding proteins (C/EBP) b and d Activate osteocalcin gene transcription and synergize with Runx2 at the C/EBP element to regulate bone-specific expression. J Biol Chem 2002;277:1316-23.
84. McCarthy TL, Ji C, Chen Y, Kim KK, Imagawa M, Ito Y, et al. Runt domain factor (Runx)-dependent effects on CCAAT/enhancer-binding protein delta expression and activity in osteoblasts. J Biol Chem 2000;275:21746-53.
85. Selvamurugan N, Chou WY, Pearman AT, Pulumati MR, Partridge NC. Parathyroid hormone regulates the rat collagenase-3 promoter in osteoblastic cells through the cooperative interaction of the activator protein-1 site and the runt domain binding sequence. J Biol Chem 1998;273:10647-57.
86. Harrison JR, Huang YF, Wilson KA, Kelly PL, Adams DJ, Gronowicz GA, et al. Col1a1 promoter-targeted expression of p20C/EBPbeta , a truncated C/EBPbeta isoform, causes osteopenia in transgenic mice. J Biol Chem 2005;280:8117-24.
87. Pereira RC, Stadmeyer L, Marciniak SJ, Ron D, Canalis E. C/EBP homologous protein is necessary for normal osteoblastic function. J Cell Biochem 2006;97:633-40.
88. Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell 2004;117:387-98.
89. Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, et al. Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 2000;6:985-90.
90. Jochum W, David JP, Elliott C, Wutz A, Plenk Jr H, Matsuo K, et al. Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat Med 2000;6:980-4.
91. Banerjee C, Stein JL, van Wijnen AJ, Frenkel B, Lian JB, Stein GS. Transforming growth factor-beta 1 responsiveness of the rat osteocalcin gene is mediated by an activator protein-1 binding site. Endocrinology 1996;137:1991-2000.
92. Naito J, Kaji H, Sowa H, Hendy GN, Sugimoto T, Chihara K. Menin suppresses osteoblast differentiation by antagonizing the AP-1 factor, JunD. J Biol Chem 2005;280:4785-91.
93. Aslam F, McCabe L, Frenkel B, van Wijnen AJ, Stein GS, Lian JB, et al. AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation. Endocrinology 1999;140:63-70.
94. McCabe LR, Banerjee C, Kundu R, Harrison RJ, Dobner PR, Stein JL, et al. Developmental expression and activities of specific fos and jun proteins are functionally related to osteoblast maturation: role of fra-2 and jun D during differentiation. Endocrinology 1996;137:4398-408.
95. Zaidi SK, Sullivan AJ, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites. Proc Natl Acad Sci USA 2002;99:8048-53.
96. Afzal F, Pratap J, Ito K, Ito Y, Stein JL, van Wijnen AJ, et al. Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription. J Cell Physiol 2005;204:63-72.
97. Alliston T, Choy L, Ducy P, Karsenty G, Derynck R. TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J 2001;20:2254-72.
98. Kang JS, Alliston T, Delston R, Derynck R. Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J 2005;24:2543-55.
99. Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, et al. A RUNX2/PEBP2aA/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc Natl Acad Sci USA 2000;97:10549-54.
100. Zhang YW, Yasui N, Kakazu N, Abe T, Takada K, Imai S, et al. PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients. Gene 2000;244:21-8.
101. Young DW, Pratap J, Javed A, Weiner B, Ohkawa Y, van Wijnen A, et al. SWI/SNF chromatin remodeling complex is obligatory for BMP2-induced, Runx2-dependent skeletal gene expression that controls osteoblast differentiation. J Cell Biochem 2005;94:720-30.
102. Franceschi RT, Xiao G. Regulation of the osteoblast-specific transcription factor, Runx2: Responsiveness to multiple signal transduction pathways. J Cell Biochem 2003;88:446-54.
103. Kojima H, Uemura T. Strong and rapid induction of osteoblast differentiation by Cbfa1/Til-1 overexpression for bone regeneration. J Biol Chem 2005;280:2944-53.
104. Byers BA, Guldberg RE, Garcia AJ. Synergy between genetic and tissue engineering: Runx2 overexpression and in vitro construct development enhance in vivo mineralization. Tissue Eng 2004;10:1757-66.
105. Geoffroy V, Kneissel M, Fournier B, Boyde A, Matthias P. High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol Cell Biol 2002;22:6222-33.
106. Liu W, Toyosawa S, Furuichi T, Kanatani N, Yoshida C, Liu Y, et al. Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol 2001;155:157-66.
107. Ueta C, Iwamoto M, Kanatani N, Yoshida C, Liu Y, Enomoto-Iwamoto M, et al. Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol 2001;153:87-100.
108. Zhao M, Qiao M, Harris SE, Oyajobi BO, Mundy GR, Chen D. Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. J Biol Chem 2004;279:12854-9.
109. Shen R, Chen M, Wang YJ, Kaneki H, Xing L, O'Keefe RJ, et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem 2006;281:3569-76.
110. Kaneki H, Guo R, Chen D, Yao Z, Schwarz EM, Zhang YE, et al. Tumor necrosis factor promotes Runx2 degradation through upregulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 2006;281:4326-33.
111. Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, et al. Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem 2003;278:50259-72.
112. Xiao G, Jiang D, Gopalakrishnan R, Franceschi RT. Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J Biol Chem 2002;277:36181-7.
113. Nusse R. Wnt signaling in disease and in development. Cell Res 2005;15:28-32.
114. Yang Y. Wnts and wing: wnt signaling in vertebrate limb development and musculoskeletal morphogenesis. Birth Defects Res Part C Embryo Today 2003;69:305-17.
115. Church VL, Francis-West P. Wnt signalling during limb development. Int J Dev Biol 2002;46:927-36.
116. Hartmann C, Tabin CJ. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell 2001;104:341-51.
117. Hartmann C, Tabin CJ. Dual roles of wnt signaling during chondrogenesis in the chicken limb. Development 2000;127:3141-59.
118. Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 2005;102:3324-9.
119. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;346:1513-21.
120. Little RD, Recker RR, Johnson ML. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;347:943-4.
121. Ai M, Heeger S, Bartels CF, Schelling DK. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet 2005;77:741-53.
122. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001;107:513-23.
123. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 2002;157:303-14.
124. Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, et al. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 2003;18:960-74.
125. Clement-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssiere B, Belleville C, et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci USA 2005;102:17406-11.
126. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 2005;8:739-50.
127. Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 2005;8:727-38.
128. Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, et al. Essential role of beta -catenin in post natal bone acquisition. J Biol Chem 2005;280:21162-8.
129. Li X, Liu P, Liu W, Maye P, Zhang J, Zhang Y, et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 2005;37:945-52.
130. Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell 2001;1:423-34.
131. van der Horst G, van der Werf SM, Farih-Sips H, Van Bezooijen RL, Lowik CW, Karperien M. Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells. J Bone Miner Res 2005;20:1867-77.
132. Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert AJ, Goad MB, et al. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol 2004;18:1222-37.
133. Bodine PV, Billiard J, Moran RA, Ponce-de-Leon H, McLarney S, Mangine A, et al. The Wnt antagonist secreted frizzled-related protein-1 controls osteoblast and osteocyte apoptosis. J Cell Biochem 2005;96:1212-30.
134. Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS, et al. Canonical WNT signaling promotes osteogenesis by directly stimulating RUNX2 gene expression. J Biol Chem 2005;280:33132-40.
135. Gaur T, Lengner CJ, Hussain S, Trevant B, Ayers D, Stein JL, et al. Secreted frizzled protein 1 regulates Wnt signaling for BMP induced chondrocyte differentiation. J Cell Physiol [Epub ahead of print] 2006.
136. Yu HM, Jerchow B, Sheu TJ, Liu B, Costantini F, Puzas JE, et al. The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development 2005;132:1995-2005.
137. Poole KE, Van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 2005;19:1842-4.
138. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005;280:19883-7.
139. Sevetson B, Taylor S, Pan Y. Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST). J Biol Chem 2004;279:13849-58.
140. Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem 2006;281:6203-10.
141. Zamurovic N, Cappellen D, Rohner D, Susa M. Coordinated activation of Notch, Wnt and TGF-beta signaling pathways in BMP-2 induced osteogenesis: notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. J Biol Chem 2004;279:37704-15.
142. Rawadi G, Vayssiere B, Dunn F, Baron R, Roman-Roman S. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res 2003;18:1842-53.
143. Bain G, Muller T, Wang X, Papkoff J. Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction. Biochem Biophys Res Commun 2003;301:84-91.
144. Mbalaviele G, Sheikh S, Stains JP, Salazar VS, Cheng SL, Chen D, et al. Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem 2005;94:403-18.
145. Yang L, Yamasaki K, Shirakata Y, Dai X, Tokumaru S, Yahata Y, et al. Bone morphogenetic protein-2 modulates Wnt and frizzled expression and enhances the canonical pathway of Wnt signaling in normal keratinocytes. J Dermatol Sci [Epub ahead of print] 2006.
146. Shimogori T, Banuchi V, Ng HY, Strauss JB, Grove EA. Embryonic signaling centers expressing BMP, WNT and FGF proteins interact to pattern the cerebral cortex. Development 2004;131:5639-47.
147. Liu Z, Tang Y, Qiu T, Cao X, Clemens TL. A dishevelled-1/SMAD1 interaction couples WNT and BMP signaling pathways in uncommitted bone marrow stromal cells. J Biol Chem [Epub ahead of print] 2006.
148. Choi KY, Kim HJ, Lee MH, Kwon TG, Nah HD, Furuichi T, et al. Runx2 regulates FGF2-induced Bmp2 expression during cranial bone development. Dev Dyn 2005;233:115-21.
149. Aberg T, Wang XP, Kim JH, Yamashiro T, Bei M, Rice R, et al. Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Dev Biol 2004;270:76-93.
150. Schroeder TM, Jensen ED, Westendorf JJ. Runx2: a master organizer of gene transcription in developing and maturing osteoblasts. Birth Defects Res C Embryo Today 2005;75:213-25.
151. Stein GS, Lian JB, van Wijnen AJ, Stein JL, Montecino M, Javed A, et al. Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene 2004;23:4315-29.
152. Zeng C, van Wijnen AJ, Stein JL, Meyers S, Sun W, Shopland L, et al. Identification of a nuclear matrix targeting signal in the leukemia and bone-related AML/CBFa transcription factors. Proc Natl Acad Sci USA 1997;94:6746-51.
153. Zaidi SK, Javed A, Choi J-Y, van Wijnen AJ, Stein JL, Lian JB, et al. A specific targeting signal directs Runx2/Cbfa1 to subnuclear domains and contributes to transactivation of the osteocalcin gene. J Cell Sci 2001;114:3093-102.
154. Dworetzky SI, Wright KL, Fey EG, Penman S, Lian JB, Stein JL, et al. Sequence-specific DNA-binding proteins are components of a nuclear matrix-attachment site. Proc Natl Acad Sci USA 1992;89:4178-82.
155. Choi J-Y, Pratap J, Javed A, Zaidi SK, Xing L, Balint E, et al. Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development. Proc Natl Acad Sci USA 2001;98:8650-5.
156. Vradii D, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS. A point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and results in a transformation-like phenotype. Proc Natl Acad Sci U S A 2005;102:7174-9.
157. Barnes GL, Hebert KE, Kamal M, Javed A, Einhorn TA, Lian JB, et al. Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases associated osteolytic disease. Cancer Res 2004;64:4506-13.
158. Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, et al. Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci USA 2005;102:1454-9.
159. Zaidi SK, Sullivan AJ, Medina R, Ito Y, van Wijnen AJ, Stein JL, et al. Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J 2004;23:790-9.
160. Selvamurugan N, Kwok S, Partridge NC. Smad3 interacts with JunB and Cbfa1/Runx2 for transforming growth factor-beta1-stimulated collagenase-3 expression in human breast cancer cells. J Biol Chem 2004;279:27764-73.
161. Barnes GL, Javed A, Waller SM, Kamal MH, Hebert KE, Hassan MQ, et al. Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res 2003;63:2631-7.
162. Shore P. A role for Runx2 in normal mammary gland and breast cancer bone metastasis. J Cell Biochem 2005;96:484-9.
163. Brubaker KD, Vessella RL, Brown LG, Corey E. Prostate cancer expression of runt-domain transcription factor Runx2, a key regulator of osteoblast differentiation and function. Prostate 2003;56:13-22.
164. Yeung F, Law WK, Yeh CH, Westendorf JJ, Zhang Y, Wang R, et al. Regulation of human osteocalcin promoter in hormone-independent human prostate cancer cells. J Biol Chem 2002;277:2468-76.
165. Fowler M, Borazanci E, McGhee L, Pylant SW, Williams BJ, Glass J, et al. RUNX1 (AML-1) and RUNX2 (AML-3) cooperate with prostate-derived Ets factor to activate transcription from the PSA upstream regulatory region. J Cell Biochem 2006;97:1-17.
166. Yang J, Fizazi K, Peleg S, Sikes CR, Raymond AK, Jamal N, et al. Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway. Cancer Res 2001;61:5652-9.
167. Lian JB, Javed A, Zaidi SK, Lengner C, Montecino M, van Wijnen AJ, et al. Regulatory controls for osteoblast growth and differentiation: role of Runx/Cbfa/AML factors. Crit Rev Eukaryot Gene Expr 2004;14:1-41.
168. Ohkawa Y, Marfella CG, Imbalzano AN. Skeletal muscle specification by myogenin and Mef2D via the SWI/SNF ATPase Brg1. EMBO J 2006;25:490-501.
169. de la Serna I, Carlson KA, Imbalzano AN. Mammalian SWI/SNF complexes promote MyoD-mediated muscle differentiation. Nat Genet 2001;27:187-90.
170. Spencer VA, Davie JR. Role of covalent modifications of histones in regulating gene expression. Gene 1999;240:1-12.
171. Pelletier N, Champagne N, Stifani S, Yang XJ. MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2. Oncogene 2002;21:2729-40.
172. Javed A, Gutierrez S, Montecino M, van Wijnen AJ, Stein JL, Stein GS, et al. Multiple Cbfa/AML sites in the rat osteocalcin promoter are required for basal and vitamin D responsive transcription and contribute to chromatin organization. Mol Cell Biol 1999;19:7491-500.
173. Paredes CR, Gutierrez J, Gutierrez S, Allison L, Puchi M, Imschenetzky M, et al. Interaction of the 1alpha,25-dihydroxy vitamin D3 receptor at the distal promoter region of the bone-specific osteocalcin gene requires nucleosomal remodeling. Biochemistry 2002;363:667-76.
174. Sierra J, Villagra A, Paredes R, Cruzat F, Gutierrez S, Javed A, et al. Regulation of the bone-specific osteocalcin gene by p300 requires Runx2/Cbfa1 and the vitamin D3 receptor but not p300 intrinsic histone acetyltransferase activity. Mol Cell Biol 2003;23:3339-51.
175. Gutierrez S, Liu J, Javed A, Montecino M, Stein GS, Lian JB, et al. The vitamin D response element in the distal osteocalcin promoter contributes to chromatin organization of the proximal regulatory domain. J Biol Chem 2004;279:43581-8.
176. McCarthy TL, Chang WZ, Liu Y, Centrella M. Runx2 integrates estrogen activity in osteoblasts. J Biol Chem 2003;278:43121-9.
177. Schroeder TM, Kahler RA, Li X, Westendorf JJ. Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation. J Biol Chem 2004;279:41998-2007.
178. Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, et al. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 2004;119:555-66.
179. Cui CB, Cooper LF, Yang X, Karsenty G, Aukhil I. Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol Cell Biol 2003;23:1004-13.
180. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 2005;309:1074-8.
181. Wang W, Wang YG, Reginato AM, Glotzer DJ, Fukai N, Plotkina S, et al. Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and modulates its activity during postnatal growth in mice. Dev Biol 2004;270:364-81.
182. McLarren KW, Lo R, Grbavec D, Thirunavukkarasu K, Karsenty G, Stifani S. The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor cbfa1. J Biol Chem 2000;275:530-8.
183. McLarren KW, Theriault FM, Stifani S. Association with the nuclear matrix and interaction with groucho and RUNX proteins regulate the transcription repression activity of the basic helix loop helix factor Hes1. J Biol Chem 2001;276:1578-84.
184. Jones DC, Wein MN, Oukka M, Hofstaetter JG, Glimcher MJ, Glimcher LH. Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3. Science 2006;312:1223-7.