Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Bone morphogenetic protein receptors and their nuclear effectors in bone formation

  • Chapter
Bone Morphogenetic Proteins: Regeneration of Bone and Beyond

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Pioneering studies on the ability of extracts from decalcified bone matrix to promote ectopic bone and cartilage formation [1] led to searches for the identity of these morphogens which define skeletal patterning. With the advent of powerful methods for protein purification, capability to determine amino acid sequences on small amounts of protein and DNA cloning, bone morphogenetic proteins (BMPs) were discovered [2-4]. The amino acid sequences predicted from their cDNA sequences revealed that BMP-2, BMP-3 and BMP-4 (BMP-1 is a member of the astacin family of metalloproteases) are members of the TGF-β superfamily, which also includes the TGF-βs and activins [5]. Mainly through their sequence homology with other BMPs, approximately 20 members in the BMP subgroup have now been identified and can be divided in multiple groups of structurally related proteins, e.g., BMP-2 and BMP-4 are highly related, BMP-6, BMP-7 and BMP-8 form another subgroup, and growth and differentiation factor (GDF)-5 (also termed cartilage-derived morphogenetic protein (CDMP)-1), GDF-7 (also termed CDGF-2) and GDF-7 are similar to each other. In vitro BMPs were found to have potent effects on various cells implicated in cartilage and bone formation, e.g., they induce proteoglycan synthesis in chondroblasts and stimulate alkaline phosphatase activity and type I collagen synthesis in osteoblasts [4]. When injected into muscle of rats, BMPs can induce a biological cascade of cellular events leading to ectopic bone formation [3, 4]. GDF5, GDF-6 and GDF-7 induce tendon and cartilage-like structures more efficiently [6, 7]. Preclinical studies of certain BMPs in primates and other mammals have demonstrated their effectiveness in restoring large segmental bone defects [8, 9].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Urist MR (1965) Bone: formation by autoinduction. Science 150: 893–899

    Article  CAS  Google Scholar 

  2. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242: 1528–1534

    Article  CAS  Google Scholar 

  3. Sampath TK, Maliakal JC, Hauschka PV, Jones WK, Sasak H, Tucker RF, White KH, Coughlin JE, Tucker MM, Pang RH et al (1992) Recombinant human osteogenic protein-1 (h0P-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem 267: 20352–20362

    CAS  Google Scholar 

  4. Vukicevic S, Luyten FP, Reddi AH (1989) Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin. Proc Natl Acad Sci USA 86: 8793–8797

    Article  CAS  Google Scholar 

  5. Massagué J (1990) The transforming growth factor-β family. Annu Rev Cell Biol 6: 597–641

    Article  Google Scholar 

  6. Hotten GC, Matsumoto T, Kimura M, Bechtold RF, Kron R, Ohara T, Tanaka H, Satoh Y, Okazaki M, Shirai T, Pan H, Kawai S, Pohl JS, Kudo A (1996) Recombinant human growth/differentiation factor 5 stimulates mesenchyme aggregation and chondrogenesis responsible for the skeletal development of limbs. Growth Factors 13: 65–74

    Article  CAS  Google Scholar 

  7. Wolfman NM, Hattersley G, Cox K, Celeste AJ, Nelson R, Yamaji N, Dube JL, DiBlasio-Smith E, Nove J, Song JJ et al (1997) Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-β gene family. J Clin Invest 100: 321–330

    Article  CAS  Google Scholar 

  8. Reddi AH (1994) Symbiosis of biotechnology and biomaterials: applications in tissue engineering of bone and cartilage. J Cell Biochem 56: 192–195

    Article  CAS  Google Scholar 

  9. Reddi AH (1998) Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol 16: 247–252

    Article  CAS  Google Scholar 

  10. Cunningham NS, Paralkar V, Reddi AH (1992) Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor β mRNA expression. Proc Natl Acad Sci USA 89: 11740–11744

    Article  CAS  Google Scholar 

  11. Hogan BL (1996) Bone morphogenetic proteins in development. Curr Opin Genet Dev 6: 432–438

    Article  CAS  Google Scholar 

  12. Goumans MJ and Mummery C (2000) Functional analysis of the TGF-β receptor/Smad pathway through gene ablation in mice. Int J Dev Biol 44: 253–265

    CAS  Google Scholar 

  13. Kingsley DM, Bland AE, Grubber JM, Marker PC, Russell LB, Copeland NG, Jenkins NA (1992) The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF β superfamily. Cell 71: 399–410

    Article  CAS  Google Scholar 

  14. Storm EE, Huynh TV, Copeland NG, Jenkins NA, Kingsley DM, Lee SJ (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGF β superfamily. Nature 368: 639–643

    Article  CAS  Google Scholar 

  15. McPherron AC and Lee SJ (1997) Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 94: 12457–12461

    Article  CAS  Google Scholar 

  16. Thomas JT, Lin K, Nandedkar M, Camargo M, Cervenka J, Luyten FP (1996) A human chondrodysplasia due to a mutation in a TGF-β superfamily member. Nat Genet 12: 315–317

    Article  CAS  Google Scholar 

  17. Massagué J (1998) TGF-β signal transduction. Annu Rev Biochem 67: 753–791

    Article  Google Scholar 

  18. Heldin CH, Miyazono K, ten Dijke P (1997) TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465–471

    Article  CAS  Google Scholar 

  19. Mathews LS and Vale WW (1991) Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell 65: 973–982

    Article  CAS  Google Scholar 

  20. Lin HY, Wang XF, Ng-Eaton E, Weinberg RA, Lodish HF (1992) Expression cloning of the TGF-β type II receptor, a functional transmembrane serine/threonine kinase. Cell 68: 775–785

    Article  CAS  Google Scholar 

  21. Ebner R, Chen RH, Shum L, Lawler S, Zioncheck TF, Lee A, Lopez AR, Derynck R (1993) Cloning of a type I TGF-β receptor and its effect on TGF-β binding to the type II receptor. Science 260: 1344–1348

    Article  CAS  Google Scholar 

  22. Attisano L, Carcamo J, Ventura F, Weis FM, Massagué J, Wrana JL (1993) Identification of human activin and TGF β type I receptors that form heteromeric kinase complexes with type II receptors. Cell 75: 671–680

    Article  CAS  Google Scholar 

  23. Franzen P, ten Dijke P, Ichijo H, Yamashita H, Schulz P, Heldin CH, Miyazono K (1993) Cloning of a TGF β type I receptor that forms a heteromeric complex with the TGF p type II receptor. Cell 75: 681–692

    Article  CAS  Google Scholar 

  24. ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyazono K (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269: 16985–16988

    Google Scholar 

  25. ten Dijke P, Yamashita H, Ichijo H, Franzén P, Laiho M, Miyazono K, Heldin CH (1994) Characterization of type I receptors for transforming growth factor-β and activin. Science 264: 101–104

    Article  Google Scholar 

  26. Nohno T, Ishikawa T, Saito T, Hosokawa K, Noji S, Wolsing DH, Rosenbaum JS (1995) Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J Biol Chem 270: 22522–22526

    Article  CAS  Google Scholar 

  27. Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K (1995) Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA 92: 7632–7636

    Article  CAS  Google Scholar 

  28. Liu F, Ventura F, Doody J, Massagué J (1995) Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 15: 3479–3486

    CAS  Google Scholar 

  29. Koenig BB, Cook JS, Wolsing DH, Ting J, Tiesman JP, Correa PE, Olson CA, Pecquet AL, Ventura F, Grant RA (1994) Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol 14: 5961–5974

    CAS  Google Scholar 

  30. Yamashita H, ten Dijke P, Huylebroeck D, Sampath TK, Andries M, Smith JC, Heldin CH, Miyazono K (1995) Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects. J Cell Biol 130: 217–226

    Article  CAS  Google Scholar 

  31. ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K (1993) Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 8: 2879–2887

    CAS  Google Scholar 

  32. Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J (1994) Mechanism of activation of the TGF-β receptor. Nature 370: 341–347

    Article  CAS  Google Scholar 

  33. Miettinen PJ, Ebner R, Lopez AR, Derynck R (1994) TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127: 2021–2036

    Article  CAS  Google Scholar 

  34. Macías-Silva M, Hoodless PA, Tang SJ, Buchwald M, Wrana JL (1998) Specific activation of Smadl signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem 273: 25628–25636

    Article  Google Scholar 

  35. Armes NA and Smith JC (1997) The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not cooperate to establish thresholds. Development 124: 3797–3804

    CAS  Google Scholar 

  36. Nishitoh H, Ichijo H, Kimura M, Matsumoto T, Makishima F, Yamaguchi A, Yamashita H, Enomoto S, Miyazono K (1996) Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. J Biol Chem 271: 21345–21352

    Article  CAS  Google Scholar 

  37. Akiyama S, Katagiri T, Namiki M, Yamaji N, Yamamoto N, Miyama K, Shibuya H, Ueno N, Wozney JM, Suda T (1997) Constitutively active BMP type I receptors trans-duce BMP-2 signals without the ligand in C2C12 myoblasts. Exp Cell Res 235: 362–369

    Article  CAS  Google Scholar 

  38. Namiki M, Akiyama S, Katagiri T, Suzuki A, Ueno N, Yamaji N, Rosen V, Wozney JM, Suda T (1997) A kinase domain-truncated type I receptor blocks bone morphogenetic protein-2-induced signal transduction in C2C12 myoblasts. J Biol Chem 272: 22046–22052

    Article  CAS  Google Scholar 

  39. Chen D, Ji X, Harris MA, Feng JQ, Karsenty G, Celeste AJ, Rosen V, Mundy GR, Harris SE (1998) Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 142: 295–305

    Article  CAS  Google Scholar 

  40. 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: 3801–3813

    CAS  Google Scholar 

  41. Daluiski A, Engstrand T, Bahamonde ME, Gamer LW, Agius E, Stevenson SL, Cox K, Rosen V, Lyons KM (2001) Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet 27: 84–88

    CAS  Google Scholar 

  42. Gu Z, Reynolds EM, Song J, Lei H, Feijen A, Yu L, He W, MacLaughlin DT, van den Eijnden-van Raaij, Donahoe PK et al (1999) The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo. Development 126: 2551–2561

    CAS  Google Scholar 

  43. Verschueren K, Dewulf N, Goumans MJ, Lonnoy O, Feijen A, Grimsby S, Vandi Spiegle K, ten Dijke P, Moren A, Vanscheeuwijck P et al (1995) Expression of type I and type IB receptors for activin in midgestation mouse embryos suggests distinct functions in organogenesis. Mech Dev 52: 109–123

    Article  CAS  Google Scholar 

  44. Dewulf N, Verschueren K, Lonnoy O, Moral A, Grimsby S, Vande Spiegle K, Miyazono K, Huylebroeck D, ten Dijke P (1995) Distinct spatial and temporal expression patterns of two type I receptors for bone morphogenetic proteins during mouse embryogenesis. Endocrinology 136: 2652–2663

    Article  CAS  Google Scholar 

  45. Zou H, Wieser R, Massagué J, Niswander L (1997) Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev 11: 2191–2203

    Article  CAS  Google Scholar 

  46. Yi SE, Daluiski A, Pederson R, Rosen V, Lyons KM (2000) The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 127: 621–630

    CAS  Google Scholar 

  47. Manova K, De Leon V, Angeles M, Kalantry S, Giarre M, Attisano L, Wrana J, Bachvarova RF (1995) mRNAs for activin receptors II and IIB are expressed in mouse oocytes and in the epiblast of pregastrula and gastrula stage mouse embryos. Mech Dev 49: 3–11

    Article  CAS  Google Scholar 

  48. Matzuk MM, Kumar TR, Bradley A (1995) Different phenotypes for mice deficient in either activins or activin receptor type II. Nature 374: 356–360

    Article  CAS  Google Scholar 

  49. Beppu H, Kawabata M, Hamamoto T, Chytil A, Minowa O, Noda T, Miyazono K (2000) BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev Biol 221: 249–258

    Article  CAS  Google Scholar 

  50. Roelen BA, Goumans MJ, van Rooijen MA, Mummery CL (1997) Differential expression of BMP receptors in early mouse development. Int J Dev Biol 41: 541–549

    CAS  Google Scholar 

  51. Yonemori K, Imamura T, Ishidou Y, Okano T, Matsunaga S, Yoshida H, Kato M, Sam-path TK, Miyazono K, ten Dijke P et al (1997) Bone morphogenetic protein receptors and activin receptors are highly expressed in ossified ligament tissues of patients with ossification of the posterior longitudinal ligament. Am J Pathol 150: 1335–1347

    CAS  Google Scholar 

  52. Sakou T, Onishi T, Yamamoto T, Nagamine T, Sampath T, ten Dijke P (1999) Localization of Smads, the TGF-β family intracellular signaling components during endochondral ossification. J Bone Miner Res 14: 1145–1152

    Article  CAS  Google Scholar 

  53. Ishidou Y, Kitajima I, Obama H, Maruyama I, Murata F, Imamura T, Yamada N, ten Dijke P, Miyazono K, Sakou T (1995) Enhanced expression of type I receptors for bone morphogenetic proteins during bone formation. J Bone Miner Res 10: 1651–1659

    Article  CAS  Google Scholar 

  54. Hayashi K, Ishidou Y, Yonemori K, Nagamine T, Origuchi N, Maeda S, Imamura T, Kato M, Yoshida H, Sampath TK et al (1997) Expression and localization of bone morphogenetic proteins (BMPs) and BMP receptors in ossification of the ligamentum flavum. Bone 21: 23–30

    Article  CAS  Google Scholar 

  55. Okano T, Ishidou Y, Kato M, Imamura T, Yonemori K, Origuchi N, Matsunaga S, Yoshida H, ten Dijke P, Sakou T (1997) Orthotopic ossification of the spinal ligaments of Zucker fatty rats: a possible animal model for ossification of the human posterior longitudinal ligament. J Orthop Res 15: 820–829

    Article  CAS  Google Scholar 

  56. Mishina Y, Suzuki A, Ueno N, Behringer RR (1995) Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev 9: 3027–3037

    Article  CAS  Google Scholar 

  57. Winnier G, Blessing M, Labosky PA, Hogan BL (1995) Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev 9: 2105–2116

    Article  CAS  Google Scholar 

  58. Oh SP, Li E (1997) The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11: 1812–1826

    Article  CAS  Google Scholar 

  59. Song J, Oh SP, Schrewe H, Nomura M, Lei H, Okano M, Gridley T, Li E (1999) The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev Biol 213: 157–169

    Article  CAS  Google Scholar 

  60. Gilboa L, Nohe A, Geissendorfer T, Sebald W, Henis YI, Knaus P (2000) Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 11: 1023–1035

    CAS  Google Scholar 

  61. Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massagué J (1992) TGF β signals through a heteromeric protein kinase receptor complex. Cell 71: 1003–1014

    Article  CAS  Google Scholar 

  62. Carcamo J, Weis FM, Ventura F, Wieser R, Wrana JL, Attisano L, Massagué J (1994) Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor 13 and activin. Mol Cell Biol 14: 3810–3821

    CAS  Google Scholar 

  63. Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massagué J (1998) Determinants of specificity in TGF-β signal transduction. Genes Dev 12: 2144–2152

    Article  CAS  Google Scholar 

  64. Feng XH, Derynck R (1997) A kinase subdomain of transforming growth factor-β (TGF-β) type I receptor determines the TGF-β intracellular signaling specificity. EMBO J 16: 3912–3923

    Article  CAS  Google Scholar 

  65. Persson U, Izumi H, Souchelnytskyi S, Itoh S, Grimsby S, Engstrom U, Heldin CH, Funa K, ten Dijke P (1998) The L45 loop in type I receptors for TGF-β family members is a critical determinant in specifying Smad isoform activation. FEBS Lett 434: 83–87

    Article  CAS  Google Scholar 

  66. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26: 81–84

    Article  CAS  Google Scholar 

  67. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA, Newman J, Williams D, Galie N et al (2001) BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 68: 92–102

    Article  CAS  Google Scholar 

  68. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P et al (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family. J Med Genet 37: 741–745

    Article  CAS  Google Scholar 

  69. Wilkins MR, Gibbs JS, Shovlin CL (2000) A gene for primary pulmonary hypertension. Lancet 356: 1207–1208

    Article  CAS  Google Scholar 

  70. Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massagué J, Bernard O, Soosairaiah J (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 162: 1089–1098

    Article  CAS  Google Scholar 

  71. Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM (1995) Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139: 1347–1358

    CAS  Google Scholar 

  72. Savage C, Das P, Finelli AL, Townsend SR, Sun CY, Baird SE, Padgett RW (1996) Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor β pathway components. Proc Natl Acad Sci USA 93: 790–794

    Article  CAS  Google Scholar 

  73. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K (1997) Smad6 inhibits signalling by the TGF-β superfamily. Nature 389: 622–626

    Article  CAS  Google Scholar 

  74. Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH et al (1997) Identification of Smad7, a TGF13-inducible antagonist of TGF-β signalling. Nature 389: 631–635

    Article  CAS  Google Scholar 

  75. Lo RS, Chen YG, Shi Y, Pavletich NP, Massagué J (1998) The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-β receptors. EMBO J 17: 996–1005

    Article  CAS  Google Scholar 

  76. Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFβ receptor. Cell 95: 779–791

    Article  CAS  Google Scholar 

  77. Miura S, Takeshita T, Asao H, Kimura Y, Murata K, Sasaki Y, Hanai JI, Beppu H, Tsukazaki T, Wrana JL et al (2000) Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol Cell Biol 20: 9346–9355

    Article  CAS  Google Scholar 

  78. Abdollah S, Macias-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wrana JL (1997) TI3RI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem 272: 27678–27685

    Article  CAS  Google Scholar 

  79. Kretzschmar M, Liu F, Hata A, Doody J, Massagué J (1997) The TGF-3 family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev 11: 984–995

    Article  CAS  Google Scholar 

  80. Souchelnytskyi S, Tamaki K, Engstrom U, Wernstedt C, ten Dijke P, Heldin CH (1997) Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-β signaling. J Biol Chem 272: 28107–28115

    Article  CAS  Google Scholar 

  81. Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T (1999) Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. J Cell Sci 112: 3519–3527

    CAS  Google Scholar 

  82. 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: 1872–1879

    Article  CAS  Google Scholar 

  83. Tamaki K, Souchelnytskyi S, Itoh S, Nakao A, Sampath K, Heldin CH, ten Dijke P (1998) Intracellular signaling of osteogenic protein-1 through Smad5 activation. J Cell Physiol 177: 355–363

    Article  CAS  Google Scholar 

  84. Lagna G, Hata A, Hemmati-Brivanlou A, Massagué J (1996) Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways. Nature 383: 832–836

    Article  CAS  Google Scholar 

  85. Correia JJ, Chacko BM, Lam SS, Lin K (2001) Sedimentation studies reveal a direct role of phosphorylation in Smad3:Smad4 homo-and hetero-trimerization. Biochemistry 40: 1473–1482

    Article  CAS  Google Scholar 

  86. Kawabata M, Inoue H, Hanyu A, Imamura T, Miyazono K (1998) Smad proteins exist as monomers in vivo and undergo homo-and hetero-oligomerization upon activation by serine/threonine kinase receptors. EMBO J 17: 4056–4065

    Article  CAS  Google Scholar 

  87. Shi Y, Hata A, Lo RS, Massagué J, Pavletich NP (1997) A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature 388: 87–93

    Article  CAS  Google Scholar 

  88. Xiao Z, Liu X, Henis YI, Lodish HF (2000) A distinct nuclear localization signal in the N terminus of Smad 3 determines its ligand-induced nuclear translocation. Proc Natl Acad Sci USA 97: 7853–7858

    Article  CAS  Google Scholar 

  89. Xiao Z, Liu X, Lodish HF (2000) Importin l mediates nuclear translocation of Smad 3. J Biol Chem 275: 23425–23428

    Article  CAS  Google Scholar 

  90. Pierreux CE, Nicolas FJ, Hill CS (2000) Transforming growth factor n-independent shuttling of Smad4 between the cytoplasm and nucleus. Mol Cell Biol 20: 9041–9054

    Article  CAS  Google Scholar 

  91. Watanabe M, Masuyama N, Fukuda M, Nishida E (2000) Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal. EMBO Rep 1: 176–182

    Article  CAS  Google Scholar 

  92. Massagué J, Wotton D (2000) Transcriptional control by the TGF-β/Smad signaling system. EMBO J 19: 1745–1754

    Article  Google Scholar 

  93. ten Dijke P, Miyazono K, Heldin CH (2000) Signaling inputs converge on nuclear effectors in TGF-β signaling. Trends Biochem Sci 25: 64–70

    Article  Google Scholar 

  94. Flanders KC, Kim ES, Roberts AB (2001) Immunohistochemical expression of Smads 16 in the 15-day gestation mouse embryo: signaling by BMPs and TGF-βs. Dev Dyn 220: 141–154

    Article  CAS  Google Scholar 

  95. Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, Cheung A, Hahn S, Wakeham A, Schwartz L, Kern SE et al (1998) The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 12: 107–119

    Article  CAS  Google Scholar 

  96. Zhu H, Kaysak P, Abdollah S, Wrana JL, Thomsen GH (1999) A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400: 687–693

    Article  CAS  Google Scholar 

  97. Zhao M, Qiao M, Harris SE, Oyajobi BO, Mundy GR, Chen D (2003) Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. J Biol Chem; in press

    Google Scholar 

  98. Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM (1998) Direct binding of Smad3 and Smad4 to critical TGF β-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17: 3091–3100

    Article  CAS  Google Scholar 

  99. Jonk LJ, Itoh S, Heldin CH, ten Dijke P, Kruijer W (1998) Identification and functional characterization of a Smad binding element (SBE) in the JunB promoter that acts as a transforming growth factor-β, activin, and bone morphogenetic protein-inducible enhancer. J Biol Chem 273: 21145–21152

    Article  CAS  Google Scholar 

  100. Yingling JM, Datto MB, Wong C, Frederick JP, Liberati NT, Wang XF (1997) Tumor suppressor Smad4 is a transforming growth factor β-inducible DNA binding protein. Mol Cell Biol 17: 7019–7028

    CAS  Google Scholar 

  101. Korchynskyi O, ten Dijke P (2002) Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem 277: 4883–4891

    Article  CAS  Google Scholar 

  102. Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, Kern SE (1998) Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1: 611–617

    Article  CAS  Google Scholar 

  103. Lopez-Rovira T, Chalaux E, Massagué J, Rosa JL, Ventura F (2002) Direct binding of Smadl and Smad4 to two distinct motifs mediates bone morphogenetic protein-specific transcriptional activation of Id1 gene. J Biol Chem 277: 3176–3185

    Article  CAS  Google Scholar 

  104. Karaulanov E, Knochel W, Niehrs C (2004) Transcriptional regulation of BMP4 synexpression in transgenic Xenopus. EMBO J 23: 344–356

    Article  CAS  Google Scholar 

  105. Brodin G, Ahgren A, ten Dijke P, Heldin CH, Heuchel R (2000) Efficient TGF-β induction of the Smad7 gene requires cooperation between AP-1, Sp1, and Smad proteins on the mouse Smad7 promoter. J Biol Chem 275: 29023–29030

    Article  CAS  Google Scholar 

  106. Denissova NG, Pouponnot C, Long J, He D, Liu F (2000) Transforming growth factor 13-inducible independent binding of SMAD to the Smad7 promoter. Proc Natl Acad Sci USA 97: 6397–6402

    Article  CAS  Google Scholar 

  107. Nagarajan RP, Zhang J, Li W, Chen Y (1999) Regulation of Smad7 promoter by direct association with Smad3 and Smad4. J Biol Chem 274: 33412–33418

    Article  CAS  Google Scholar 

  108. Stopa M, Anhuf D, Terstegen L, Gatsios P, Gressner AM, Dooley S (2000) Participation of Smad2, Smad3, and Smad4 in transforming growth factor 13 (TGF-(3)-induced activation of Smad7. THE TGF-β response element of the promoter requires functional Smad binding element and E-box sequences for transcriptional regulation. J Biol Chem 275: 29308–29317

    Article  CAS  Google Scholar 

  109. von Gersdorff G, Susztak K, Rezvani F, Bitzer M, Liang D, Bottinger EP (2000) Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor 13. J Biol Chem 275: 11320–11326

    Article  CAS  Google Scholar 

  110. Stroschein SL, Wang W, Luo K (1999) Cooperative binding of Smad proteins to two adjacent DNA elements in the plasminogen activator inhibitor-1 promoter mediates transforming growth factor β-induced smad-dependent transcriptional activation. J Biol Chem 274: 9431–9441

    Article  CAS  Google Scholar 

  111. Chen SJ, Yuan W, Lo S, Trojanowska M, Varga J (2000) Interaction of smad3 with a proximal smad-binding element of the human a2(I) procollagen gene promoter required for transcriptional activation by TGF-β. J Cell Physiol 183: 381–392

    Article  CAS  Google Scholar 

  112. Vindevoghel L, Lechleider RJ, Kon A, de Caestecker MP, Uitto J, Roberts AB, Mauviel A (1998) SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor β Proc Natl Acad Sci USA 95: 14769–14774

    Article  CAS  Google Scholar 

  113. Shi Y, Wang YF, Jayaraman L, Yang H, Massagué J, Pavletich NP (1998) Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-β signaling. Cell 94: 585–594

    Article  CAS  Google Scholar 

  114. Henningfeld KA, Rastegar S, Adler G, Knochel W (2000) Smad1 and Smad4 are components of the bone morphogenetic protein-4 (BMP-4)-induced transcription complex of the Xvent-2B promoter. J Biol Chem 275: 21827–21835

    Article  CAS  Google Scholar 

  115. Kim J, Johnson K, Chen HJ, Carroll S, Laughon A (1997) Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature 388: 304–308

    Article  CAS  Google Scholar 

  116. Ishida W, Hamamoto T, Kusanagi K, Yagi K, Kawabata M, Takehara K, Sampath TK, Kato M, Miyazono K (2000) Smad6 is a Smad1/5-induced smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter. J Biol Chem 275: 6075–6079

    Article  CAS  Google Scholar 

  117. Kusanagi K, Inoue H, Ishidou Y, Mishima HK, Kawabata M, Miyazono K (2000) Characterization of a bone morphogenetic protein-responsive Smad-binding element. Mol Biol Cell 11: 555–565

    CAS  Google Scholar 

  118. Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, Hosoda E, Imamura T, Kuno J, Yamashita T et al (2000) Negative Regulation of BMP/Smad Signaling by Tob in Osteoblasts. Cell 103: 1085–1097

    Article  CAS  Google Scholar 

  119. Benchabane H, Wrana JL (2003) GATA- and Smad1-dependent enhancers in the Smad7 gene differentially interpret bone morphogenetic protein concentrations. Mol Cell Biol 23: 6646–6661

    Article  CAS  Google Scholar 

  120. Itoh F, Itoh S, Goumans MJ, Valdimarsdottir G, Iso T, Dotto GP, Hamamori Y, Kedes L, Kato M, Dijke Pt P (2004) Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells. EMBO J 23: 541–551

    Article  CAS  Google Scholar 

  121. Derynck R, Zhang Y, Feng XH (1998) Smads: transcriptional activators of TGF-β responses. Cell 95: 737–740

    Article  CAS  Google Scholar 

  122. Hata A, Seoane J, Lagna G, Montalvo E, Hemmati-Brivanlou A, Massagué J (2000) OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell 100: 229–240

    Article  CAS  Google Scholar 

  123. Hanai J, Chen LF, Kanno T, Ohtani-Fujita N, Kim WY, Guo WH, Imamura T, Ishidou Y, Fukuchi M, Shi MJ et al (1999) Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Ca promoter. J Biol Chem 274: 31577–31582

    Article  CAS  Google Scholar 

  124. Pardali E, Xie XQ, Tsapogas P, Itoh S, Arvanitidis K, Heldin CH, ten Dijke P, Grundstrom T, Sideras P (2000) Smad and AML proteins synergistically confer transforming growth factor β1 responsiveness to human germ-line IgA genes. J Biol Chem 275: 3552–3560

    Article  CAS  Google Scholar 

  125. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M et al (1997) Targeted disruption of Cbfal results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89: 755–764

    Article  CAS  Google Scholar 

  126. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G (1999) A Cbfal-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13: 1025–1036

    Article  CAS  Google Scholar 

  127. Mundlos S, Mulliken JB, Abramson DL, Warman ML, Knoll JH, Olsen BR (1995) Genetic mapping of cleidocranial dysplasia and evidence of a microdeletion in one family. Hum Mol Genet 4: 71–75

    CAS  Google Scholar 

  128. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH et al (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89: 773–779

    Article  CAS  Google Scholar 

  129. Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, Nogami H, Ochi T, Miyazono K, Ito Y (2000) A RUNX2/PEBP2a A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc Natl Acad Sci USA 97: 10549–10554

    Article  CAS  Google Scholar 

  130. Liu F, Hata A, Baker JC, Doody J, Carcamo J, Harland RM, Massagué J (1996) A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 381: 620–623

    Article  CAS  Google Scholar 

  131. Meersseman G, Verschueren K, Nelles L, Blumenstock C, Kraft H, Wuytens G, Remade J, Kozak CA, Tylzanowski P, Niehrs C et al (1997) The C-terminal domain of Mad-like signal transducers is sufficient for biological activity in the Xenopus embryo and transcriptional activation. Mech Dev 61: 127–140

    Article  CAS  Google Scholar 

  132. Pouponnot C, Jayaraman L, Massagué J (1998) Physical and functional interaction of SMADs and p300/CBP. J Biol Chem 273: 22865–22868

    Article  CAS  Google Scholar 

  133. Yahata T, de Caestecker MP, Lechleider RJ, Andriole S, Roberts AB, Isselbacher KJ, Shioda T (2000) The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors. J Biol Chem 275: 8825–8834

    Article  CAS  Google Scholar 

  134. Postigo AA, Depp JL, Taylor JJ, Kroll KL (2003) Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. EMBO J 22: 2453–2462

    Article  CAS  Google Scholar 

  135. Postigo AA (2003) Opposing functions of ZEB proteins in the regulation of the TGF13/BMP signaling pathway. EMBO J 22: 2443–2452

    Article  CAS  Google Scholar 

  136. Bai RY, Koester C, Ouyang T, Hahn SA, Hammerschmidt M, Peschel C, Duyster J (2002) SMIF, a Smad4-interacting protein that functions as a co-activator in TGFβ signalling. Nat Cell Biol 4: 181–190

    Article  CAS  Google Scholar 

  137. Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284: 479–482

    Article  CAS  Google Scholar 

  138. Piccolo S, Sasai Y, Lu B, De Robertis EM (1996) Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 86: 589–598

    Article  CAS  Google Scholar 

  139. Zimmerman LB, Jesus-Escobar JM, Harland RM (1996) The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86: 599–606

    Article  CAS  Google Scholar 

  140. Hsu DR, Economides AN, Wang X, Eimon PM, Harland RM (1998) The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol Cell 1: 673–683

    Article  CAS  Google Scholar 

  141. Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis EM (1999) The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397: 707–710

    Article  CAS  Google Scholar 

  142. Yokouchi Y, Vogan KJ, Pearse RV, Tabin CJ (1999) Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell 98: 573–583

    Article  CAS  Google Scholar 

  143. Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T, Shimasaki S, Sugino H, Ueno N (1998) Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc Natl Acad Sci USA 95: 9337–9342

    Article  CAS  Google Scholar 

  144. Canalis E, Economides AN, Gazzerro E (2003) Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 24: 218–235

    Article  CAS  Google Scholar 

  145. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10: 537–543

    Article  CAS  Google Scholar 

  146. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y et al (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68: 577–589

    Article  CAS  Google Scholar 

  147. Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, Thesleff I, Itoh N (2003) Sclerostin is a novel secreted osteoblast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem 278: 24113–24117

    Article  CAS  Google Scholar 

  148. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K et al (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22: 6267–6276

    Article  CAS  Google Scholar 

  149. van Bezooijen RL, Roelen BAJ, Visser A, Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Lowik CWGM (2004) Sclerostin is an osteocyteexpressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199: 805–814

    Article  CAS  Google Scholar 

  150. Oelgeschlager M, Larrain J, Geissert D, De Robertis EM (2000) The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature 405: 757–763

    Article  CAS  Google Scholar 

  151. Rawadi G, Vayssiere B, Dunn F, Baron R, Roman-Roman S (2003) BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res 18: 1842–1853

    Article  CAS  Google Scholar 

  152. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B et al (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70: 11–19

    Article  CAS  Google Scholar 

  153. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346: 1513–1521

    Article  CAS  Google Scholar 

  154. Itasaki N, Jones CM, Mercurio S, Rowe A, Domingos PM, Smith JC, Krumlauf R (2003) Wise, a context-dependent activator and inhibitor of Wnt signalling. Development 130: 4295–4305

    Article  CAS  Google Scholar 

  155. Degen WG, Weterman MA, van Groningen JJ, Cornelissen IM, Lemmers JP, Agterbos MA, Geurts van Kessel A, Swart GW, Bloemers HP (1996) Expression of nma, a novel gene, inversely correlates with the metastatic potential of human melanoma cell lines and xenografts. Int J Cancer 65: 460–465

    Article  CAS  Google Scholar 

  156. Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massagué J, Niehrs C (1999) Silencing of TGF-β signalling by the pseudoreceptor BAMBI. Nature 401: 480–485

    Article  CAS  Google Scholar 

  157. Tsang M, Kim R, de Caestecker MP, Kudoh T, Roberts AB, Dawid IB (2000) Zebrafish nma is involved in TGFβ family signaling. Genesis 28: 47–57

    Article  CAS  Google Scholar 

  158. Ishisaki A, Yamato K, Hashimoto S, Nakao A, Tamaki K, Nonaka K, ten Dijke P, Sugino H, Nishihara T (1999) Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein-and activin-mediated growth arrest and apoptosis in B cells. J Biol Chem 274: 13637–13642

    Article  CAS  Google Scholar 

  159. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL et al (1997) The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFI3 signaling. Cell 89: 1165–1173

    Article  CAS  Google Scholar 

  160. Kaysak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol Cell 6: 1365–1375

    Article  Google Scholar 

  161. Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K (2001) Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276: 12477–12480

    Article  CAS  Google Scholar 

  162. Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A (1998) Smad6 inhibits BMP/ Smadl signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12: 186–197

    Article  CAS  Google Scholar 

  163. Bai S, Shi X, Yang X, Cao X (2000) Smad6 as a transcriptional corepressor. J Biol Chem 275: 8267–8270

    Article  CAS  Google Scholar 

  164. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T (2000) BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 275: 17647–17652

    Article  CAS  Google Scholar 

  165. Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (2001) Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J 20: 4132–4142

    Article  CAS  Google Scholar 

  166. Ibarrola N, Kratchmarova I, Nakajima D, Schiemann WP, Moustakas A, Pandey A, Mann M (2004) Cloning of a novel signaling molecule, AMSH-2, that potentiates transforming growth factor R signaling. BMC Cell Biol 5: 2

    Article  Google Scholar 

  167. Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q (1999) The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling. Genes Dev 13: 2196–2206

    Article  CAS  Google Scholar 

  168. Wang W, Mariani FV, Harland RM, Luo K (2000) Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proc Natl Acad Sci USA 97: 14394–14399

    Article  CAS  Google Scholar 

  169. Verschueren K, Remade JE, Collart C, Kraft H, Baker BS, Tylzanowski P, Nelles L, Wuytens G, Su MT, Bodmer R et al (1999) SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5’-CACCT sequences in candidate target genes. J Biol Chem 274: 20489–20498

    Article  CAS  Google Scholar 

  170. Osada S, Ohmori SY, Taira M (2003) XMAN1, an inner nuclear membrane protein, antagonizes BMP signaling by interacting with Smad1 in Xenopus embryos. Development 130: 1783–1794

    Article  CAS  Google Scholar 

  171. Li L, Xin H, Xu X, Huang M, Zhang X, Chen Y, Zhang S, Fu XY, Chang Z (2004) CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription. Mol Cell Biol 24: 856–864

    Article  CAS  Google Scholar 

  172. Kretzschmar M, Doody J, Massagué J (1997) Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389: 618–622

    Article  CAS  Google Scholar 

  173. Shen ZJ, Nakamoto T, Tsuji K, Nifuji A, Miyazono K, Komori T, Hirai H, Noda M (2002) Negative regulation of bone morphogenetic protein/Smad signaling by Cas-interacting zinc finger protein in osteoblasts. J Biol Chem 277: 29840–29846

    Article  CAS  Google Scholar 

  174. Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270: 2008–2011

    Article  CAS  Google Scholar 

  175. Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K (1999) XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1–TAK1 in the BMP signaling pathway. EMBO J 18: 179–187

    Article  CAS  Google Scholar 

  176. Sano Y, Harada J, Tashiro S, Gotoh-Mandeville R, Maekawa T, Ishii S (1999) ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factorβ signaling. J Biol Chem 274: 8949–8957

    Article  CAS  Google Scholar 

  177. Nakamura K, Shirai T, Morishita S, Uchida S, Saeki-Miura K, Makishima F (1999) p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDCS cells. Exp Cell Res 250: 351–363

    Article  CAS  Google Scholar 

  178. 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: 871–880

    CAS  Google Scholar 

  179. Katagiri T, Yamaguchi A, Komaki M, Abe E, Takahashi N, Ikeda T, Rosen V, Wozney JM, Fujisawa-Sehara A, Suda T (1994) Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol 127: 1755–1766

    Article  CAS  Google Scholar 

  180. Maliakal JC, Asahina I, Hauschka PV, Sampath TK (1994) Osteogenic protein-1 (BMP7) inhibits cell proliferation and stimulates the expression of markers characteristic of osteoblast phenotype in rat osteosarcoma (17/2.8) cells. Growth Factors 11: 227–234

    Article  CAS  Google Scholar 

  181. Lee KS, Kim HJ, Li QL, Chi XZ, Ueta C, Komori T, Wozney JM, Kim EG, Choi JY, Ryoo HM et al (2000) Runx2 is a common target of transforming growth factor pi 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: 8783–8792

    Article  CAS  Google Scholar 

  182. Shi X, Yang X, Chen D, Chang Z, Cao X (1999) Smad1 interacts with homeobox DNA-binding proteins in bone morphogenetic protein signaling. J Biol Chem 274: 13711–13717

    Article  CAS  Google Scholar 

  183. Yang X, Ji X, Shi X, Cao X (2000) Smad1 domains interacting with Hoxc-8 induce osteoblast differentiation. J Biol Chem 275: 1065–1072

    Article  CAS  Google Scholar 

  184. Hullinger TG, Pan Q, Viswanathan HL, Somerman MJ (2001) TGF13 and BMP-2 activation of the OPN promoter: roles of smad-and hox-binding elements. Exp Cell Res 262: 69–74

    Article  CAS  Google Scholar 

  185. Wan M, Shi X, Feng X, Cao X (2001) Transcriptional mechanisms of BMP-induced osteoprotegrin gene expression. J Biol Chem 276: 10119–10125

    Article  CAS  Google Scholar 

  186. Nakanishi T, Kimura Y, Tamura T, Ichikawa H, Yamaai Y, Sugimoto T, Takigawa M (1997) Cloning of a mRNA preferentially expressed in chondrocytes by differential display-PCR from a human chondrocytic cell line that is identical with connective tissue growth factor (CTGF) mRNA. Biochem Biophys Res Commun 234: 206–210

    Article  CAS  Google Scholar 

  187. Nishida T, Nakanishi T, Asano M, Shimo T, Takigawa M (2000) Effects of CTGF/Hcs24, a hypertrophic chondrocyte-specific gene product, on the proliferation and differentiation of osteoblastic cells in vitro. J Cell Physiol 184: 197–206

    Article  CAS  Google Scholar 

  188. Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130: 2779–2791

    Article  CAS  Google Scholar 

  189. Abreu JG, Ketpura NI, Reversade B, De Robertis EM (2002) Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β. Nat Cell Biol 4: 599–604

    CAS  Google Scholar 

  190. St Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13: 2072–2086

    Article  CAS  Google Scholar 

  191. Seki K, Hata A (2004) Indian hedgehog gene is a target of the bone morphogenetic protein signaling pathway. J Biol Chem 279: 18544–18549

    Article  CAS  Google Scholar 

  192. Afrakhte M, Moren A, Jossan S, Itoh S, Sampath K, Westermark B, Heldin CH, Heldin NE, ten Dijke P (1998) Induction of inhibitory Smad6 and Smad7 mRNA by TGF-β family members. Biochem Biophys Res Commun 249: 505–511

    Article  CAS  Google Scholar 

  193. Takase M, Imamura T, Sampath TK, Takeda K, Ichijo H, Miyazono K, Kawabata M (1998) Induction of Smad6 mRNA by bone morphogenetic proteins. Biochem Biophys Res Commun 244: 26–29

    Article  CAS  Google Scholar 

  194. Chalaux E, Lopez-Rovira T, Rosa JL, Bartrons R, Ventura F (1998) JunB is involved in the inhibition of myogenic differentiation by bone morphogenetic protein-2. J Biol Chem 273: 537–543

    Article  CAS  Google Scholar 

  195. Ogata T, Wozney JM, Benezra R, Noda M (1993) Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helixloop-helix molecule in osteoblast-like cells. Proc Natl Acad Sci USA 90: 9219–9222

    Article  CAS  Google Scholar 

  196. Hollnagel A, Oehlmann V, Heymer J, Ruther U, Nordheim A (1999) Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. J Biol Chem 274: 19838–19845

    Article  CAS  Google Scholar 

  197. Moldes M, Lasnier F, Feve B, Pairault J, Djian P (1997) Id3 prevents differentiation of preadipose cells. Mol Cell Biol 17: 1796–1804

    CAS  Google Scholar 

  198. Jen Y, Weintraub H, Benezra R (1992) Overexpression of Id protein inhibits the muscle differentiation program: in vivo association of Id with E2A proteins. Genes Dev 6: 1466–1479

    Article  CAS  Google Scholar 

  199. Melnikova IN and Christy BA (1996) Muscle cell differentiation is inhibited by the helix-loop-helix protein Id3. Cell Growth Differ 7: 1067–1079

    CAS  Google Scholar 

  200. 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: 123–133

    Article  CAS  Google Scholar 

  201. Acampora D, Merlo GR, Paleari L, Zerega B, Postiglione MP, Mantero S, Bober E, Barbieri O, Simeon A, Levi G (1999) Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene DlxS. Development 126: 3795–3809

    CAS  Google Scholar 

  202. Chiba S, Takeshita K, Imai Y, Kumano K, Kurokawa M, Masuda S, Shimizu K, Nakamura S, Ruddle FH, Hirai H (2003) Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling pathway from activin A in hematopoietic cells. Proc Natl Acad Sci USA 100: 15577–15582

    Article  CAS  Google Scholar 

  203. Sirard C, Kim S, Mirtsos C, Tadich P, Hoodless PA, Itie A, Maxson R, Wrana JL, Mak TW (2000) Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor β-related signaling. J Biol Chem 275: 2063–2070

    Article  CAS  Google Scholar 

  204. Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, Maeda T, Takano Y, Uchiyama M, Heaney S et al (2000) Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 24: 391–395

    Article  CAS  Google Scholar 

  205. Wahl M, Shukunami C, Heinzmann U, Hamajima K, Hiraki Y, Imai K (2004) Transcriptome analysis of early chondrogenesis in ATDCS cells induced by bone morphogenetic protein 4. Genomics 83: 45–58

    Article  CAS  Google Scholar 

  206. Peng Y, Kang Q, Cheng H, Li X, Sun MH, Jiang W, Luu HH, Park JY, Haydon RC, He TC (2003) Transcriptional characterization of bone morphogenetic proteins (BMPs)- mediated osteogenic signaling. J Cell Biochem 90: 1149–1165

    Article  CAS  Google Scholar 

  207. Korchynskyi O, Dechering KJ, Sijbers AM, Olijve W, ten Dijke P (2003) Gene array analysis of bone morphogenetic protein type I receptor-induced osteoblast differentiation. J Bone Miner Res 18: 1177–1185

    Article  CAS  Google Scholar 

  208. Balint E, Lapointe D, Drissi H, van der Meijden C, Young DW, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2003) Phenotype discovery by gene expression profiling: mapping of biological processes linked to BMP-2-mediated osteoblast differentiation. J Cell Biochem 89: 401–426

    Article  CAS  Google Scholar 

  209. Vaes BL, Dechering KJ, Feijen A, Hendriks JM, Lefevre C, Mummery CL, Olijve W, van Zoelen EJ, Steegenga WT (2002) Comprehensive microarray analysis of bone morphogenetic protein 2-induced osteoblast differentiation resulting in the identification of novel markers for bone development. J Bone Miner Res 17: 2106–2118

    Article  CAS  Google Scholar 

  210. de Jong DS, van Zoelen EJ, Bauerschmidt S, Olijve W, Steegenga WT (2002) Microarray analysis of bone morphogenetic protein, transforming growth factor βand activin early response genes during osteoblastic cell differentiation. J Bone Miner Res 17: 2119–2129

    Article  Google Scholar 

  211. Gu K, Zhang L, Jin T, Rutherford RB (2004) Identification of potential modifiers of Runx2/Cbfal activity in C2C12 cells in response to bone morphogenetic protein-7. Cells Tissues Organs 176: 28–40

    Article  CAS  Google Scholar 

  212. Service RF (2000) Tissue engineers build new bone. Science 289: 1498–1500

    Article  CAS  Google Scholar 

  213. Franceschi RT, Wang D, Krebsbach PH, Rutherford RB (2000) Gene therapy for bone formation: in vitro and in vivo osteogenic activity of an adenovirus expressing BMP7. J Cell Biochem 78: 476–486

    Article  CAS  Google Scholar 

  214. Fang J, Zhu YY, Smiley E, Bonadio J, Rouleau JP, Goldstein SA, McCauley LK, Davidson BL, Roessler BJ (1996) Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci USA 93: 5753–5758

    Article  CAS  Google Scholar 

  215. Zhang H, Bradley A (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122: 2977–2986

    CAS  Google Scholar 

  216. Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL, Robertson EJ (1998) Mice lacking Bmp6 function. Dev Genet 22: 321–339

    Article  CAS  Google Scholar 

  217. Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 9: 2808–2820

    Article  CAS  Google Scholar 

  218. Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 9: 2795–2807

    Article  CAS  Google Scholar 

  219. Solloway MJ, Robertson EJ (1999) Early embryonic lethality in BmpS;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup. Development 126: 1753–1768

    CAS  Google Scholar 

  220. Zhao GQ, Deng K, Labosky PA, Liaw L, Hogan BL (1996) The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse. Genes Dev 10: 1657–1669

    Article  CAS  Google Scholar 

  221. Galloway SM, McNatty KP, Cambridge LM, Laitinen MP, Juengel JL, Jokiranta TS, McLaren RJ, Luiro K, Dodds KG, Montgomery GW et al (2000) Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat Genet 25: 279–283

    Article  CAS  Google Scholar 

  222. Lechleider RJ, Ryan JL, Garrett L, Eng C, Deng C, Wynshaw-Boris A, Roberts AB (2001) Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion. Dev Biol 240: 157–167

    Article  CAS  Google Scholar 

  223. Tremblay KD, Dunn NR, Robertson EJ (2001) Mouse embryos lacking Smadl signals display defects in extra-embryonic tissues and germ cell formation. Development 128: 3609–3621

    CAS  Google Scholar 

  224. Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk MM, Zwijsen A (1999) Smad5 knock-out mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development 126: 1631–1642

    CAS  Google Scholar 

  225. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C et al (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382: 448–452

    Article  CAS  Google Scholar 

  226. Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL (1998) Altered wound healing in mice lacking a functional osteopontin gene (sppl). J Clin Invest 101: 1468–1478

    CAS  Google Scholar 

  227. Yoshitake H, Rittling SR, Denhardt DT, Noda M (1999) Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption. Proc Natl Acad Sci USA 96: 8156–8160

    Article  CAS  Google Scholar 

  228. Willing MC, Pruchno CJ, Atkinson M, Byers PH (1992) Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen. Am J Hum Genet 51: 508–515

    CAS  Google Scholar 

  229. Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Milian JL, MacGregor GR et al (1999) Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res 14: 2015–2026

    Article  CAS  Google Scholar 

  230. Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN, Fairchild-Huntress V, Dixon KL, Dunmore JH, Gimbrone MA et al (2000) A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet 24: 171–174

    Article  CAS  Google Scholar 

  231. Lyden D, Young AZ, Zagzag D, Yan W, Gerald W, O’Reilly R, Bader BL, Hynes RO, Zhuang Y, Manova K et al (1999) Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401: 670–677

    Article  CAS  Google Scholar 

  232. Schorpp-Kistner M, Wang ZQ, Angel P, Wagner EF (1999) JunB is essential for mammalian placentation. EMBO J 18: 934–948

    Article  CAS  Google Scholar 

  233. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89: 747–754

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Olexander Korchynskyi, Rutger L. van Bezooijen & Peter ten Dijke

  2. Thurston Arthritis Research Center and Department of Rheumatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

    Olexander Korchynskyi

  3. Department of Endodontics, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina, USA

    Olexander Korchynskyi

  4. Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

    Rutger L. van Bezooijen & Clemens W. G. M. Löwik

Authors
  1. Olexander Korchynskyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rutger L. van Bezooijen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clemens W. G. M. Löwik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter ten Dijke
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Laboratory for Mineralized Tissues, School of Medicine, Salata 11, Zagreb, HR, 10000, Croatia

    Slobodan Vukicevic

  2. Genzyme Corporation, One Mountain Road, Framingham, MA, 01701-9322, USA

    Kuber T. Sampath

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Basel AG

About this chapter

Cite this chapter

Korchynskyi, O., van Bezooijen, R.L., Löwik, C.W.G.M., Dijke, P.t. (2004). Bone morphogenetic protein receptors and their nuclear effectors in bone formation. In: Vukicevic, S., Sampath, K.T. (eds) Bone Morphogenetic Proteins: Regeneration of Bone and Beyond. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-7857-9_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-7857-9_2

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9598-9

  • Online ISBN: 978-3-0348-7857-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation