Signal transduction and transcriptional regulation during mesenchymal cell differentiation

  • Riko Nishimura
  • Kenji Hata
  • Fumiyo Ikeda
  • Fumitaka Ichida
  • Atsuko Shimoyama
  • Takuma Matsubara
  • Masahiro Wada
  • Katsuhiko Amano
  • Toshiyuki Yoneda
Review Article

Key words

osteoblast adipocyte chondrocyte bone morphogenetic protein 

References

  1. 1.
    Karsenty G (2003) The complexities of skeletal biology. Nature (Lond) 423:316–318CrossRefGoogle Scholar
  2. 2.
    Grigoriadis AE, Heersche JN, Aubin JE (1988) Differentiation of muscle, fat, cartilage, and bone from progenitor cells present in a bone-derived clonal cell population: effect of dexamethasone. J Cell Biol 106:2139–2151PubMedCrossRefGoogle Scholar
  3. 3.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedCrossRefGoogle Scholar
  4. 4.
    Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764PubMedCrossRefGoogle Scholar
  5. 5.
    Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771PubMedCrossRefGoogle Scholar
  6. 6.
    Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29PubMedCrossRefGoogle Scholar
  7. 7.
    de Crombrugghe B, Lefebvre V, Nakashima K (2001) Regulatory mechanisms in the pathways of cartilage and bone formation. Curr Opin Cell Biol 13:721–727PubMedCrossRefGoogle Scholar
  8. 8.
    Kronenberg HM (2003) Developmental regulation of the growth plate. Nature (Lond) 423:332–336CrossRefGoogle Scholar
  9. 9.
    Komori T (2006) Regulation of osteoblast differentiation by transcription factors. J Cell Biochem 99:1233–1239PubMedCrossRefGoogle Scholar
  10. 10.
    Morrison RF, Farmer SR (1999) Insights into the transcriptional control of adipocyte differentiation. J Cell Biochem Suppl 32–33:59–67CrossRefGoogle Scholar
  11. 11.
    Spiegelman BM (1998) PPAR-gamma in monocytes: less pain, any gain? Cell 93:153–155PubMedCrossRefGoogle Scholar
  12. 12.
    Li X, Cao X (2006) BMP signaling and skeletogenesis. Ann N Y Acad Sci 1068:26–40PubMedCrossRefGoogle Scholar
  13. 13.
    Nishimura R, Hata K, Ikeda F, Matsubara T, Yamashita K, Ichida F, Yoneda T (2003) The role of Smads in BMP signaling. Front Biosci 8:s275–s284PubMedCrossRefGoogle Scholar
  14. 14.
    Yamaguchi A, Komori T, Suda T (2000) Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocr Rev 21:393–411PubMedCrossRefGoogle Scholar
  15. 15.
    Zhao M, Harris SE, Horn D, Geng Z, Nishimura R, Mundy GR, Chen D (2002) Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. J Cell Biol 157:1049–1060PubMedCrossRefGoogle Scholar
  16. 16.
    Nishimura R, Kato Y, Chen D, Harris SE, Mundy GR, Yoneda T (1998) Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J Biol Chem 273:1872–1879PubMedCrossRefGoogle Scholar
  17. 17.
    Fujii M, Takeda K, Imamura T, Aoki H, Sampath TK, Enomoto S, Kawabata M, Kato M, Ichijo H, Miyazono K (1999) Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol Biol Cell 10: 3801–3813PubMedGoogle Scholar
  18. 18.
    Hanai J, Chen LF, Kanno T, Ohtani-Fujita N, Kim WY, Guo WH, Imamura T, Ishidou Y, Fukuchi M, Shi MJ, Stavnezer J, Kawabata M, Miyazono K, Ito Y (1999) Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter. J Biol Chem 274:31577–31582PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, Nogami H, Ochi T, Miyazono K, Ito Y (2000) A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc Natl Acad Sci U S A 97:10549–10554PubMedCrossRefGoogle Scholar
  20. 20.
    Lee KS, Kim HJ, Li QL, Chi XZ, Ueta C, Komori T, Wozney JM, Kim EG, Choi JY, Ryoo HM, Bae SC (2000) Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol Cell Biol 20: 8783–8792PubMedCrossRefGoogle Scholar
  21. 21.
    Nishimura R, Hata K, Harris SE, Ikeda F, Yoneda T (2002) Core-binding factor alpha 1 (Cbfa1) induces osteoblastic differentiation of C2C12 cells without interactions with Smad1 and Smad5. Bone (NY) 31:303–312Google Scholar
  22. 22.
    Alliston T, Choy L, Ducy P, Karsenty G, Derynck R (2001) TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J 20:2254–2272PubMedCrossRefGoogle Scholar
  23. 23.
    Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, Hosoda E, Imamura T, Kuno J, Yamashita T, Miyazono K, Noda M, Noda T, Yamamoto T (2000) Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103:1085–1097PubMedCrossRefGoogle Scholar
  24. 24.
    Cheng SL, Shao JS, Charlton-Kachigian N, Loewy AP, Towler DA (2003) MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J Biol Chem 278:45969–45977PubMedCrossRefGoogle Scholar
  25. 25.
    Ichida F, Nishimura R, Hata K, Matsubara T, Ikeda F, Hisada K, Yatani H, Cao X, Komori T, Yamaguchi A, Yoneda T (2004) Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. J Biol Chem 279:34015–34022PubMedCrossRefGoogle Scholar
  26. 26.
    Shirakabe K, Terasawa K, Miyama K, Shibuya H, Nishida E (2001) Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5. Genes Cells 6:851–856PubMedCrossRefGoogle Scholar
  27. 27.
    Kim YJ, Lee MH, Wozney JM, Cho JY, Ryoo HM (2004) Bone morphogenetic protein-2-induced alkaline phosphatase expression is stimulated by Dlx5 and repressed by Msx2. J Biol Chem 279:50773–50780PubMedCrossRefGoogle Scholar
  28. 28.
    Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, Maeda T, Takano Y, Uchiyama M, Heaney S, Peters H, Tang Z, Maxson R, Maas R (2000) Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 24:391–395PubMedCrossRefGoogle Scholar
  29. 29.
    Wilkie AO, Tang Z, Elanko N, Walsh S, Twigg SR, Hurst JA, Wall SA, Chrzanowska KH, Maxson RE Jr (2000) Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nat Genet 24:387–390PubMedCrossRefGoogle Scholar
  30. 30.
    Miyama K, Yamada G, Yamamoto TS, Takagi C, Miyado K, Sakai M, Ueno N, Shibuya H (1999) A BMP-inducible gene, dlx5, regulates osteoblast differentiation and mesoderm induction. Dev Biol 208:123–133PubMedCrossRefGoogle Scholar
  31. 31.
    Acampora D, Merlo GR, Paleari L, Zerega B, Postiglione MP, Mantero S, Bober E, Barbieri O, Simeone A, Levi G (1999) Craniofacial, vestibular and bone defects in mice lacking the Distalless-related gene Dlx5. Development (Camb) 126:3795–3809Google Scholar
  32. 32.
    Robledo RF, Rajan L, Li X, Lufkin T (2002) The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. Genes Dev 16:1089–1101PubMedCrossRefGoogle Scholar
  33. 33.
    Xu SC, Harris MA, Rubenstein JL, Mundy GR, Harris SE (2001) Bone morphogenetic protein-2 (BMP-2) signaling to the Col2alpha1 gene in chondroblasts requires the homeobox gene Dlx-2. DNA Cell Biol 20:359–365PubMedCrossRefGoogle Scholar
  34. 34.
    Newberry EP, Latifi T, Towler DA (1998) Reciprocal regulation of osteocalcin transcription by the homeodomain proteins Msx2 and Dlx5. Biochemistry 37:16360–16368PubMedCrossRefGoogle Scholar
  35. 35.
    Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523PubMedCrossRefGoogle Scholar
  36. 36.
    Gregorieff A, Clevers H (2005) Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev 19:877–890PubMedCrossRefGoogle Scholar
  37. 37.
    Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature (Lond) 434:843–850CrossRefGoogle Scholar
  38. 38.
    Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (2006) Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res 21:1738–1749PubMedCrossRefGoogle Scholar
  39. 39.
    van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, Quax PH, Vrieling H, Papapoulos SE, ten Dijke P, Lowik CW (2007) Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 22:19–28PubMedCrossRefGoogle Scholar
  40. 40.
    Johnson ML, Harnish K, Nusse R, Van Hul W (2004) LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res 19:1749–1757PubMedCrossRefGoogle Scholar
  41. 41.
    Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, Kharode Y, Sauter L, Babij P, Brown EL, Hill AA, Akhter MP, Johnson ML, Recker RR, Komm BS, Bex FJ (2006) Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 281:31720–31728PubMedCrossRefGoogle Scholar
  42. 42.
    Yang Y, Topol L, Lee H, Wu J (2003) Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development (Camb) 130:1003–1015CrossRefGoogle Scholar
  43. 43.
    Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314PubMedCrossRefGoogle Scholar
  44. 44.
    Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature (Lond) 407:535–538CrossRefGoogle Scholar
  45. 45.
    Kokubu C, Heinzmann U, Kokubu T, Sakai N, Kubota T, Kawai M, Wahl MB, Galceran J, Grosschedl R, Ozono K, Imai K (2004) Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development (Camb) 131:5469–5480CrossRefGoogle Scholar
  46. 46.
    Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278–1282PubMedCrossRefGoogle Scholar
  47. 47.
    Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, Deng L, Clemens TL, Williams BO (2005) Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem 280:21162–21168PubMedCrossRefGoogle Scholar
  48. 48.
    Glass DA II, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764PubMedCrossRefGoogle Scholar
  49. 49.
    Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, Yamada Y, Costantini F, Wakisaka S, Pacifici M, Iwamoto M, Enomoto-Iwamoto M (2005) Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem 280:19185–19195PubMedCrossRefGoogle Scholar
  50. 50.
    Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B (2004) Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev 18: 1072–1087PubMedCrossRefGoogle Scholar
  51. 51.
    Ingham PW (1998) Transducing Hedgehog: the story so far. EMBO J 17:3505–3511PubMedCrossRefGoogle Scholar
  52. 52.
    Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature (Lond) 383:407–413CrossRefGoogle Scholar
  53. 53.
    Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ (1996) Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273:613–622PubMedCrossRefGoogle Scholar
  54. 54.
    Kobayashi T, Soegiarto DW, Yang Y, Lanske B, Schipani E, McMahon AP, Kronenberg HM (2005) Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP. J Clin Invest 115:1734–1742PubMedCrossRefGoogle Scholar
  55. 55.
    Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y, Komori T (2004) Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev 18:952–963PubMedCrossRefGoogle Scholar
  56. 56.
    Long F, Chung UI, Ohba S, McMahon J, Kronenberg HM, McMahon AP (2004) Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development (Camb) 131:1309–1318CrossRefGoogle Scholar
  57. 57.
    Denef N, Neubuser D, Perez L, Cohen SM (2000) Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102:521–531PubMedCrossRefGoogle Scholar
  58. 58.
    Mullor JL, Sanchez P, Altaba AR (2002) Pathways and consequences: Hedgehog signaling in human disease. Trends Cell Biol 12:562–569PubMedCrossRefGoogle Scholar
  59. 59.
    Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H (1999) Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development (Camb) 126:3915–3924Google Scholar
  60. 60.
    Lamm ML, Catbagan WS, Laciak RJ, Barnett DH, Hebner CM, Gaffield W, Walterhouse D, Iannaccone P, Bushman W (2002) Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev Biol 249:349–366PubMedCrossRefGoogle Scholar
  61. 61.
    Pan Y, Bai CB, Joyner AL, Wang B (2006) Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 26:3365–3377PubMedCrossRefGoogle Scholar
  62. 62.
    Bhatia N, Thiyagarajan S, Elcheva I, Saleem M, Dlugosz A, Mukhtar H, Spiegelman VS (2006) Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. J Biol Chem 281:19320–19326PubMedCrossRefGoogle Scholar
  63. 63.
    Tempe D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP (2006) Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCF-beta TrCP. Mol Cell Biol 26:4316–4326PubMedCrossRefGoogle Scholar
  64. 64.
    Murone M, Luoh SM, Stone D, Li W, Gurney A, Armanini M, Grey C, Rosenthal A, de Sauvage FJ (2000) Gli regulation by the opposing activities of fused and suppressor of fused. Nat Cell Biol 2:310–312PubMedCrossRefGoogle Scholar
  65. 65.
    Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC (1998) Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet 20:54–57PubMedCrossRefGoogle Scholar
  66. 66.
    Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH, Joyner AL, Hui C (1997) Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development (Camb) 124:113–123Google Scholar
  67. 67.
    Hui CC, Joyner AL (1993) A mouse model of greig cephalopoly-syndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet 3:241–246PubMedCrossRefGoogle Scholar
  68. 68.
    Shimoyama A, Wada M, Ikeda F, Hata K, Matsubara T, Nifuji A, Noda M, Amano K, Yamaguchi A, Nishimura R, Yoneda T (2007) Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol Biol Cell 18:2411–2418PubMedCrossRefGoogle Scholar
  69. 69.
    Zhao M, Qiao M, Harris SE, Chen D, Oyajobi BO, Mundy GR (2006) The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling. Mol Cell Biol 26:6197–6208PubMedCrossRefGoogle Scholar
  70. 70.
    Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G, Harris SE, Gallwitz W, Kim KB, Hu S, Crews CM, Mundy GR (2003) Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest 111:1771–1782PubMedGoogle Scholar
  71. 71.
    Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–779PubMedCrossRefGoogle Scholar
  72. 72.
    Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754PubMedCrossRefGoogle Scholar
  73. 73.
    Harada H, Tagashira S, Fujiwara M, Ogawa S, Katsumata T, Yamaguchi A, Komori T, Nakatsuka M (1999) Cbfa1 isoforms exert functional differences in osteoblast differentiation. J Biol Chem 274:6972–6978PubMedCrossRefGoogle Scholar
  74. 74.
    Liu W, Toyosawa S, Furuichi T, Kanatani N, Yoshida C, Liu Y, Himeno M, Narai S, Yamaguchi A, Komori T (2001) Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol 155:157–166PubMedCrossRefGoogle Scholar
  75. 75.
    Geoffroy V, Kneissel M, Fournier B, Boyde A, Matthias P (2002) High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol Cell Biol 22:6222–6233PubMedCrossRefGoogle Scholar
  76. 76.
    Enomoto H, Enomoto-Iwamoto M, Iwamoto M, Nomura S, Himeno M, Kitamura Y, Kishimoto T, Komori T (2000) Cbfa1 is a positive regulatory factor in chondrocyte maturation. J Biol Chem 275:8695–8702PubMedCrossRefGoogle Scholar
  77. 77.
    Yoshida CA, Furuichi T, Fujita T, Fukuyama R, Kanatani N, Kobayashi S, Satake M, Takada K, Komori T (2002) Core-binding factor beta interacts with Runx2 and is required for skeletal development. Nat Genet 32:633–638.PubMedCrossRefGoogle Scholar
  78. 78.
    Ueta C, Iwamoto M, Kanatani N, Yoshida C, Liu Y, Enomoto-Iwamoto M, Ohmori T, Enomoto H, Nakata K, Takada K, Kurisu K, Komori T (2001) Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol 153:87–100PubMedCrossRefGoogle Scholar
  79. 79.
    Gutierrez S, Javed A, Tennant DK, van Rees M, Montecino M, Stein GS, Stein JL, Lian JB (2002) CCAAT/enhancer-binding proteins (C/EBP) beta and delta activate osteocalcin gene transcription and synergize with Runx2 at the C/EBP element to regulate bone-specific expression. J Biol Chem 277:1316–1323PubMedCrossRefGoogle Scholar
  80. 80.
    Hata K, Nishimura R, Ueda M, Ikeda F, Matsubara T, Ichida F, Hisada K, Nokubi T, Yamaguchi A, Yoneda T (2005) A CCAAT/enhancer binding protein beta isoform, liver-enriched inhibitory protein, regulates commitment of osteoblasts and adipocytes. Mol Cell Biol 25:1971–1979PubMedCrossRefGoogle Scholar
  81. 81.
    Cui CB, Cooper LF, Yang X, Karsenty G, Aukhil I (2003) Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol Cell Biol 23:1004–1013PubMedCrossRefGoogle Scholar
  82. 82.
    Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G (2004) A twist code determines the onset of osteoblast differentiation. Dev Cell 6:423–435PubMedCrossRefGoogle Scholar
  83. 83.
    Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K, Takayanagi H (2005) NFAT and Osterix cooperatively regulate bone formation. Nat Med 11:880–885PubMedCrossRefGoogle Scholar
  84. 84.
    Winslow MM, Pan M, Starbuck M, Gallo EM, Deng L, Karsenty G, Crabtree GR (2006) Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 10:771–782PubMedCrossRefGoogle Scholar
  85. 85.
    Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, Hanauer A, Karsenty G (2004) ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell 117:387–398PubMedCrossRefGoogle Scholar
  86. 86.
    Ruther U, Komitowski D, Schubert FR, Wagner EF (1989) c-fos expression induces bone tumors in transgenic mice. Oncogene 4:861–865PubMedGoogle Scholar
  87. 87.
    Grigoriadis AE, Schellander K, Wang ZQ, Wagner EF (1993) Osteoblasts are target cells for transformation in c-fos transgenic mice. J Cell Biol 122:685–701PubMedCrossRefGoogle Scholar
  88. 88.
    Jochum W, David JP, Elliott C, Wutz A, Plenk H Jr, Matsuo K, Wagner EF (2000) Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat Med 6:980–984PubMedCrossRefGoogle Scholar
  89. 89.
    Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (2000) Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 6:985–990PubMedCrossRefGoogle Scholar
  90. 90.
    Eferl R, Hoebertz A, Schilling AF, Rath M, Karreth F, Kenner L, Amling M, Wagner EF (2004) The Fos-related antigen Fra-1 is an activator of bone matrix formation. EMBO J 23:2789–2799PubMedCrossRefGoogle Scholar
  91. 91.
    Lefebvre V, Huang W, Harley VR, Goodfellow PN, de Crombrugghe B (1997) SOX9 is a potent activator of the chondrocytespecific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 17:2336–2346PubMedGoogle Scholar
  92. 92.
    McDowall S, Argentaro A, Ranganathan S, Weller P, Mertin S, Mansour S, Tolmie J, Harley V (1999) Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. J Biol Chem 274:24023–24030PubMedCrossRefGoogle Scholar
  93. 93.
    Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (1999) Sox9 is required for cartilage formation. Nat Genet 22:85–89PubMedCrossRefGoogle Scholar
  94. 94.
    Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16: 2813–2828PubMedCrossRefGoogle Scholar
  95. 95.
    Kawakami Y, Tsuda M, Takahashi S, Taniguchi N, Esteban CR, Zemmyo M, Furumatsu T, Lotz M, Belmonte JC, Asahara H (2005) Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9. Proc Natl Acad Sci U S A 102:2414–2419PubMedCrossRefGoogle Scholar
  96. 96.
    Burkhardt R, Kettner G, Bohm W, Schmidmeier M, Schlag R, Frisch B, Mallmann B, Eisenmenger W, Gilg T (1987) Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. Bone (NY) 8:157–164Google Scholar
  97. 97.
    Wu Z, Xie Y, Bucher NL, Farmer SR (1995) Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. Genes Dev 7:2350–2363CrossRefGoogle Scholar
  98. 98.
    Tanaka T, Yoshida N, Kishimoto T, Akira S (1997) Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J 16:7432–7443PubMedCrossRefGoogle Scholar
  99. 99.
    Ahrens M, Ankenbauer T, Schroder D, Hollnagel A, Mayer H, Gross G (1993) Expression of human bone morphogenetic proteins-2 or-4 in murine mesenchymal progenitor C3H10T1/2 cells induces differentiation into distinct mesenchymal cell lineages. DNA Cell Biol 12:871–880PubMedGoogle Scholar
  100. 100.
    Hata K, Nishimura R, Ikeda F, Yamashita K, Matsubara T, Nokubi T, Yoneda T (2002) Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Mol Biol Cell 31:545–555Google Scholar
  101. 101.
    Jin W, Takagi T, Kanesashi SN, Kurahashi T, Nomura T, Harada J, Ishii S (2006) Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev Cell 10:461–471PubMedCrossRefGoogle Scholar
  102. 102.
    Okazaki R, Inoue D, Shibata M, Saika M, Kido S, Ooka H, Tomiyama H, Sakamoto Y, Matsumoto T (2002) Estrogen promotes early osteoblast differentiation and inhibits adipocyte differentiation in mouse bone marrow stromal cell lines that express estrogen receptor (ER) alpha or beta. Endocrinology 143:2349–2356PubMedCrossRefGoogle Scholar
  103. 103.
    Dang Z, Lowik CW (2004) The balance between concurrent activation of ERs and PPARs determines daidzein-induced osteogenesis and adipogenesis. J Bone Miner Res 19:853–861PubMedCrossRefGoogle Scholar
  104. 104.
    Suzawa M, Takada I, Yanagisawa J, Ohtake F, Ogawa S, Yamauchi T, Kadowaki T, Takeuchi Y, Shibuya H, Gotoh Y, Matsumoto K, Kato S (2003) Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. Nat Cell Biol 5:224–230PubMedCrossRefGoogle Scholar
  105. 105.
    Kaneki H, Guo R, Chen D, Yao Z, Schwarz EM, Zhang YE, Boyce BF, Xing L (2006) Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 281:4326–4333PubMedCrossRefGoogle Scholar
  106. 106.
    Manolagas SC, Almeida M (2007) Gone with the Wnts: ta-catenin, TCF, FOXO, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol Endocrinol 21:2605–2614Google Scholar
  107. 107.
    Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A 102: 3324–3329PubMedCrossRefGoogle Scholar
  108. 108.
    Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H (2004) PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 113:846–855PubMedGoogle Scholar
  109. 109.
    Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB (2005) TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309:1074–1078PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Riko Nishimura
    • 1
  • Kenji Hata
    • 1
  • Fumiyo Ikeda
    • 1
  • Fumitaka Ichida
    • 1
  • Atsuko Shimoyama
    • 1
  • Takuma Matsubara
    • 1
  • Masahiro Wada
    • 1
  • Katsuhiko Amano
    • 1
  • Toshiyuki Yoneda
    • 1
  1. 1.Department of Molecular and Cellular BiochemistryOsaka University Graduate School of DentistryOsakaJapan

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