Skip to main content
SpringerLink
Log in

Embryonic Skeletogenesis and Craniofacial Development

  • Chapter
  • First Online:
Bone Morphogenetic Proteins: Systems Biology Regulators

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

Abstract

Bone morphogenetic proteins (BMPs) are originally identified with their ability to induce heterotopic ossification. Several decades of studies have demonstrated that BMPs have pleiotropic functions in numbers of tissues for many different aspects. This review focuses on the effects of BMP signaling on skeletogenesis and craniofacial development. We will summarize recent progresses on in vitro studies, animal models, and human genetics to uncover highly context-dependent functions of BMP signaling, including unexpected outcomes, and the mechanisms of how BMP signaling regulates bone mass. We will also summarize reported findings about BMP signaling-related genes identified as causes of human diseases in skeletal system such as chondrodysplasia, facial cleft, and craniosynostosis.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

References

  1. Abe E, Yamamoto M, Taguchi Y, Lecka-Czernik B, O'Brien CA, Economides AN, Stahl N, Jilka RL, Manolagas SC (2000) Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: antagonism by noggin. J Bone Miner Res 15:663–673

    Article  CAS  PubMed  Google Scholar 

  2. Agarwal S, Loder S, Brownley C, Cholok D, Mangiavini L, Li J, Breuler C, Sung HH, Li S, Ranganathan K et al (2016) Inhibition of Hif1alpha prevents both trauma-induced and genetic heterotopic ossification. Proc Natl Acad Sci U S A 113(3):E338–E347

    Article  CAS  PubMed  Google Scholar 

  3. Agarwal S, Loder SJ, Brownley C, Eboda O, Peterson JR, Hayano S, Wu B, Zhao B, Kaartinen V, Wong VC et al (2015) BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints. Dev Biol 400:202–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alappat S, Zhang ZY, Chen YP (2003) Msx homeobox gene family and craniofacial development. Cell Res 13:429–442

    Article  CAS  PubMed  Google Scholar 

  5. Asai-Coakwell M, French CR, Ye M, Garcha K, Bigot K, Perera AG, Staehling-Hampton K, Mema SC, Chanda B, Mushegian A et al (2009) Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes. Hum Mol Genet 18:1110–1121

    Article  CAS  PubMed  Google Scholar 

  6. Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PV, Robinson JA, Bhat B et al (2003) High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18:960–974

    Article  CAS  PubMed  Google Scholar 

  7. Bain G, Muller T, Wang X, Papkoff J (2003) Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction. Biochem Biophys Res Commun 301:84–91

    Article  CAS  PubMed  Google Scholar 

  8. Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V et al (2008) Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet 82:304–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ et al (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V, Tabin CJ (2006) Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2:e216

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Bandyopadhyay A, Yadav PS, Prashar P (2013) BMP signaling in development and diseases: a pharmacological perspective. Biochem Pharmacol 85:857–864

    Article  CAS  PubMed  Google Scholar 

  13. Banerjee C, Javed A, Choi JY, Green J, Rosen V, van Wijnen AJ, Stein JL, Lian JB, Stein GS (2001) Differential regulation of the two principal Runx2/Cbfa1 n-terminal isoforms in response to bone morphogenetic protein-2 during development of the osteoblast phenotype. Endocrinology 142:4026–4039

    Article  CAS  PubMed  Google Scholar 

  14. Banse X (2002) When density fails to predict bone strength. Acta Orthop Scand Suppl 73:1–57

    PubMed  Google Scholar 

  15. Barlow AJ, Francis-West PH (1997) Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 124:391–398

    CAS  PubMed  Google Scholar 

  16. Baron R, Rawadi G, Roman-Roman S (2006) Wnt signaling: a key regulator of bone mass. Curr Top Dev Biol 76:103–127

    Article  CAS  PubMed  Google Scholar 

  17. Barrow JR, Thomas KR, Boussadia-Zahui O, Moore R, Kemler R, Capecchi MR, McMahon AP (2003) Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev 17:394–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Behr B, Panetta NJ, Longaker MT, Quarto N (2010) Different endogenous threshold levels of Fibroblast Growth Factor-ligands determine the healing potential of frontal and parietal bones. Bone 47:281–294

    Article  CAS  PubMed  Google Scholar 

  19. Bell E, Munoz-Sanjuan I, Altmann CR, Vonica A, Brivanlou AH (2003) Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor. Development 130:1381–1389

    Article  CAS  PubMed  Google Scholar 

  20. Belloni E, Muenke M, Roessler E, Traverso G, Siegel-Bartelt J, Frumkin A, Mitchell HF, Donis-Keller H, Helms C, Hing AV et al (1996) Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet 14:353–356

    Article  CAS  PubMed  Google Scholar 

  21. Bennett JH, Hunt P, Thorogood P (1995) Bone morphogenetic protein-2 and −4 expression during murine orofacial development. Arch Oral Biol 40:847–854

    Article  CAS  PubMed  Google Scholar 

  22. Bertola DR, Rodrigues MG, Quaio CR, Kim CA, Passos-Bueno MR (2013) Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation. Am J Med Genet A 161A:600–604

    Article  PubMed  CAS  Google Scholar 

  23. Beverdam A, Brouwer A, Reijnen M, Korving J, Meijlink F (2001) Severe nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice. Development 128:3975–3986

    CAS  PubMed  Google Scholar 

  24. Bhatt S, Diaz R, Trainor PA (2013) Signals and switches in Mammalian neural crest cell differentiation. Cold Spring Harb Perspect Biol 5(2)

    Google Scholar 

  25. Bonilla-Claudio M, Wang J, Bai Y, Klysik E, Selever J, Martin JF (2012) Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development. Development 139:709–719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Brown JM, Robertson KE, Wedden SE, Tickle C (1997) Alterations in Msx 1 and Msx 2 expression correlate with inhibition of outgrowth of chick facial primordia induced by retinoic acid. Anat Embryol (Berl) 195:203–207

    Article  CAS  Google Scholar 

  28. Brown JM, Wedden SE, Millburn GH, Robson LG, Hill RE, Davidson DR, Tickle C (1993) Experimental analysis of the control of expression of the homeobox-gene Msx-1 in the developing limb and face. Development 119:41–48

    CAS  PubMed  Google Scholar 

  29. Brugmann SA, Allen NC, James AW, Mekonnen Z, Madan E, Helms JA (2010) A primary cilia-dependent etiology for midline facial disorders. Hum Mol Genet 19:1577–1592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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  PubMed  PubMed Central  Google Scholar 

  31. Carano RA, Filvaroff EH (2003) Angiogenesis and bone repair. Drug Discov Today 8:980–989

    Article  CAS  PubMed  Google Scholar 

  32. Castranio T, Mishina Y (2009) Bmp2 is required for cephalic neural tube closure in the mouse. Dev Dyn 238:110–122

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chen Y, Whetstone HC, Youn A, Nadesan P, Chow EC, Lin AC, Alman BA (2007) Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation. J Biol Chem 282:526–533

    Article  CAS  PubMed  Google Scholar 

  34. Cheng H, Jiang W, Phillips FM, Haydon RC, Peng Y, Zhou L, Luu HH, An N, Breyer B, Vanichakarn P et al (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am 85-A:1544–1552

    Article  PubMed  Google Scholar 

  35. 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 383:407–413

    Article  CAS  PubMed  Google Scholar 

  36. Creuzet S, Schuler B, Couly G, Le Douarin NM (2004) Reciprocal relationships between Fgf8 and neural crest cells in facial and forebrain development. Proc Natl Acad Sci U S A 101:4843–4847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dathe K, Kjaer KW, Brehm A, Meinecke P, Nurnberg P, Neto JC, Brunoni D, Tommerup N, Ott CE, Klopocki E et al (2009) Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am J Hum Genet 84:483–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. David L, Feige JJ, Bailly S (2009) Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev 20:203–212

    Article  CAS  PubMed  Google Scholar 

  39. Davis S, Miura S, Hill C, Mishina Y, Klingensmith J (2004) BMP receptor IA is required in the mammalian embryo for endodermal morphogenesis and ectodermal patterning. Dev Biol 270:47–63

    Article  CAS  PubMed  Google Scholar 

  40. Deckers MM, van Bezooijen RL, van der Horst G, Hoogendam J, van Der Bent C, Papapoulos SE, Lowik CW (2002) Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology 143:1545–1553

    Article  CAS  Google Scholar 

  41. Degenkolbe E, Konig J, Zimmer J, Walther M, Reissner C, Nickel J, Ploger F, Raspopovic J, Sharpe J, Dathe K et al (2014) A GDF5 point mutation strikes twice--causing BDA1 and SYNS2. PLoS Genet 9:e1003846

    Article  CAS  Google Scholar 

  42. Demirhan O, Turkmen S, Schwabe GC, Soyupak S, Akgul E, Tastemir D, Karahan D, Mundlos S, Lehmann K (2005) A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies. J Med Genet 42:314–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Denker AE, Haas AR, Nicoll SB, Tuan RS (1999) Chondrogenic differentiation of murine C3H10T1/2 multipotential mesenchymal cells: I. Stimulation by bone morphogenetic protein-2 in high-density micromass cultures. Differentiation 64:67–76

    Article  CAS  PubMed  Google Scholar 

  44. Ding J, Yang L, Yan YT, Chen A, Desai N, Wynshaw-Boris A, Shen MM (1998) Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature 395:702–707

    Article  CAS  PubMed  Google Scholar 

  45. Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12:167–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dudas M, Kim J, Li WY, Nagy A, Larsson J, Karlsson S, Chai Y, Kaartinen V (2006) Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion. Dev Biol 296:298–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dudas M, Nagy A, Laping NJ, Moustakas A, Kaartinen V (2004) Tgf-beta3-induced palatal fusion is mediated by Alk-5/Smad pathway. Dev Biol 266:96–108

    Article  CAS  PubMed  Google Scholar 

  48. Dudas M, Sridurongrit S, Nagy A, Okazaki K, Kaartinen V (2004) Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells. Mech Dev 121:173–182

    Article  CAS  PubMed  Google Scholar 

  49. 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  PubMed  Google Scholar 

  50. Dwivedi PP, Grose RH, Filmus J, Hii CS, Xian CJ, Anderson PJ, Powell BC (2013) Regulation of bone morphogenetic protein signalling and cranial osteogenesis by Gpc1 and Gpc3. Bone 55:367–376

    Article  CAS  PubMed  Google Scholar 

  51. Franz-Odendaal TA (2011) Induction and patterning of intramembranous bone. Front Biosci (Landmark Ed) 16:2734–2746

    Article  CAS  Google Scholar 

  52. Fromigue O, Modrowski D, Marie PJ (2005) Apoptosis in membranous bone formation: role of fibroblast growth factor and bone morphogenetic protein signaling. Crit Rev Eukaryot Gene Expr 15:75–92

    Article  CAS  PubMed  Google Scholar 

  53. Fukuda T, Scott G, Komatsu Y, Araya R, Kawano M, Ray MK, Yamada M, Mishina Y (2006) Generation of a mouse with conditionally activated signaling through the BMP receptor, ALK2. Genesis 44:159–167

    Article  CAS  PubMed  Google Scholar 

  54. Gamer LW, Tsuji K, Cox K, Capelo LP, Lowery J, Beppu H, Rosen V (2011) BMPR-II is dispensable for formation of the limb skeleton. Genesis 49:719–724

    Article  CAS  PubMed  Google Scholar 

  55. Garimella R, Tague SE, Zhang J, Belibi F, Nahar N, Sun BH, Insogna K, Wang J, Anderson HC (2008) Expression and synthesis of bone morphogenetic proteins by osteoclasts: a possible path to anabolic bone remodeling. J Histochem Cytochem 56:569–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, Song F (2007) Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Health Technol Assess 11:1–168

    Article  CAS  PubMed  Google Scholar 

  57. Glass DA 2nd, Karsenty G (2006) Molecular bases of the regulation of bone remodeling by the canonical Wnt signaling pathway. Curr Top Dev Biol 73:43–84

    Article  CAS  PubMed  Google Scholar 

  58. Glineburg RW, Laskin DM, Blaustein DI (1982) The effects of immobilization on the primate temporomandibular joint: a histologic and histochemical study. J Oral Maxillofac Surg 40:3–8

    Article  CAS  PubMed  Google Scholar 

  59. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523

    Article  CAS  PubMed  Google Scholar 

  60. Gu S, Wu W, Liu C, Yang L, Sun C, Ye W, Li X, Chen J, Long F, Chen Y (2014) BMPRIA mediated signaling is essential for temporomandibular joint development in mice. PLoS One 9:e101000

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gu Z, Reynolds EM, Song J, Lei H, Feijen A, Yu L, He W, MacLaughlin DT, van den Eijnden-van Raaij J, 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  PubMed  Google Scholar 

  62. Gupta MC, Khan SN (2005) Application of bone morphogenetic proteins in spinal fusion. Cytokine Growth Factor Rev 16:347–355

    Article  CAS  PubMed  Google Scholar 

  63. Harada S, Rodan GA (2003) Control of osteoblast function and regulation of bone mass. Nature 423:349–355

    Article  CAS  PubMed  Google Scholar 

  64. Hartmann C (2006) A Wnt canon orchestrating osteoblastogenesis. Trends Cell Biol 16:151–158

    Article  CAS  PubMed  Google Scholar 

  65. Hatch NE (2010) FGF signaling in craniofacial biological control and pathological craniofacial development. Crit Rev Eukaryot Gene Expr 20:295–311

    Article  CAS  PubMed  Google Scholar 

  66. Hatta T, Konishi H, Katoh E, Natsume T, Ueno N, Kobayashi Y, Yamazaki T (2000) Identification of the ligand-binding site of the BMP type IA receptor for BMP-4. Biopolymers 55:399–406

    Article  CAS  PubMed  Google Scholar 

  67. Hayano S, Komatsu Y, Pan H, Mishina Y (2015) Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis. Development 142:1357–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hays E, Schmidt J, Chandar N (2009) Beta-catenin is not activated by downregulation of PTEN in osteoblasts. In Vitro Cell Dev Biol Anim 45:361–370

    Article  CAS  PubMed  Google Scholar 

  69. He F, Hu X, Xiong W, Li L, Lin L, Shen B, Yang L, Gu S, Zhang Y, Chen Y (2014) Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect. Dev Biol 391:170–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. He F, Xiong W, Wang Y, Matsui M, Yu X, Chai Y, Klingensmith J, Chen Y (2010) Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis. Dev Biol 347:109–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Henriksen K, Neutzsky-Wulff AV, Bonewald LF, Karsdal MA (2009) Local communication on and within bone controls bone remodeling. Bone 44:1026–1033

    Article  PubMed  Google Scholar 

  72. Hinton RJ (2014) Genes that regulate morphogenesis and growth of the temporomandibular joint: a review. Dev Dyn 243:864–874

    Article  CAS  PubMed  Google Scholar 

  73. Hinton RJ, Jing J, Feng JQ (2015) Genetic influences on temporomandibular joint development and growth. Curr Top Dev Biol 115:85–109

    Article  PubMed  Google Scholar 

  74. Ho CT, Lau TY, Jin Y, Lu HB, Liong E, Leung KM, Tipoe GL (2004) Overexpression of iNOS and down-regulation of BMPs-2, 4 and 7 in retinoic acid induced cleft palate formation. Histol Histopathol 19:95–104

    CAS  PubMed  Google Scholar 

  75. Hu Q, Ueno N, Behringer RR (2004) Restriction of BMP4 activity domains in the developing neural tube of the mouse embryo. EMBO Rep 5:734–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Huang QY, Li GH, Kung AW (2009) The −9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPalpha and FOXA1 binding is associated with osteoporosis. Bone 45:289–294

    Article  CAS  PubMed  Google Scholar 

  77. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W (2001) beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105:533–545

    Article  CAS  PubMed  Google Scholar 

  78. Ishii M, Merrill AE, Chan YS, Gitelman I, Rice DP, Sucov HM, Maxson RE Jr (2003) Msx2 and Twist cooperatively control the development of the neural crest-derived skeletogenic mesenchyme of the murine skull vault. Development 130:6131–6142

    Article  CAS  PubMed  Google Scholar 

  79. 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  PubMed  Google Scholar 

  80. Itoh K, Udagawa N, Katagiri T, Iemura S, Ueno N, Yasuda H, Higashio K, Quinn JM, Gillespie MT, Martin TJ et al (2001) Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand. Endocrinology 142:3656–3662

    CAS  Google Scholar 

  81. Iura A, McNerny EG, Zhang Y, Kamiya N, Tantillo M, Lynch M, Kohn DH, Mishina Y (2015) Mechanical Loading Synergistically Increases Trabecular Bone Volume and Improves Mechanical Properties in the Mouse when BMP Signaling Is Specifically Ablated in Osteoblasts. PLoS One 10:e0141345

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Jabs EW, Muller U, Li X, Ma L, Luo W, Haworth IS, Klisak I, Sparkes R, Warman ML, Mulliken JB et al (1993) A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75:443–450

    Article  CAS  PubMed  Google Scholar 

  83. Jiang X, Iseki S, Maxson RE, Sucov HM, Morriss-Kay GM (2002) Tissue origins and interactions in the mammalian skull vault. Dev Biol 241:106–116

    Article  CAS  PubMed  Google Scholar 

  84. Jing J, Hinton RJ, Feng JQ (2015) Bmpr1a signaling in cartilage development and endochondral bone formation. Vitam Horm 99:273–291

    Article  CAS  PubMed  Google Scholar 

  85. Jing J, Hinton RJ, Mishina Y, Liu Y, Zhou X, Feng JQ (2014) Critical role of Bmpr1a in mandibular condyle growth. Connect Tissue Res 55(Suppl 1):73–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jing J, Ren Y, Zong Z, Liu C, Kamiya N, Mishina Y, Liu Y, Zhou X, Feng JQ (2013) BMP receptor 1 A determines the cell fate of the postnatal growth plate. Int J Biol Sci 9:895–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jing Y, Zhou X, Han X, Jing J, von der Mark K, Wang J, de Crombrugghe B, Hinton RJ, Feng JQ (2015) Chondrocytes directly transform into bone cells in mandibular condyle growth. J Dent Res 94:1668–1675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L, Cunningham ML et al (2012) A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44:1360–1364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J (1995) Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11:415–421

    Article  CAS  PubMed  Google Scholar 

  90. Kamiya N, Jikko A, Kimata K, Damsky C, Shimizu K, Watanabe H (2002) Establishment of a novel chondrocytic cell line N1511 derived from p53-null mice. J Bone Miner Res 17:1832–1842

    Article  CAS  PubMed  Google Scholar 

  91. Kamiya N, Kaartinen VM, Mishina Y (2011) Loss-of-function of ACVR1 in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors SOST and DKK1. Biochem Biophys Res Commun 414:326–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kamiya N, Kobayashi T, Mochida Y, Yu PB, Yamauchi M, Kronenberg HM, Mishina Y (2010) Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res 25:200–210

    Article  CAS  PubMed  Google Scholar 

  93. Kamiya N, Shuxian L, Yamaguchi R, Phipps M, Aruwajoye O, Adapala NS, Yuan H, Kim HK, Feng JQ (2016 ) Targeted disruption of BMP signaling through type IA receptor (BMPR1A) in osteocyte suppresses SOST and RANKL, leading to dramatic increase in bone mass, bone mineral density and mechanical strength. Bone 91:53–63. doi: 10.1016/j.bone.2016.07.002. Epub 2016 Jul 8. PMID: 27402532

  94. Kamiya N, Ye L, Kobayashi T, Lucas DJ, Mochida Y, Yamauchi M, Kronenberg HM, Feng JQ, Mishina Y (2008) Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J Bone Miner Res 23:2007–2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kamiya N, Ye L, Kobayashi T, Mochida Y, Yamauchi M, Kronenberg HM, Feng JQ, Mishina Y (2008) BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development 135:3801–3811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kan L, Hu M, Gomes WA, Kessler JA (2004) Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype. Am J Pathol 165:1107–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kanczler JM, Oreffo RO (2008) Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater 15:100–114

    Article  CAS  PubMed  Google Scholar 

  98. Kaneko H, Arakawa T, Mano H, Kaneda T, Ogasawara A, Nakagawa M, Toyama Y, Yabe Y, Kumegawa M, Hakeda Y (2000) Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone 27:479–486

    Article  CAS  PubMed  Google Scholar 

  99. 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  PubMed  Google Scholar 

  100. Kettunen P, Nie X, Kvinnsland IH, Luukko K (2006) Histological development and dynamic expression of Bmp2-6 mRNAs in the embryonic and postnatal mouse cranial base. Anat Rec A Discov Mol Cell Evol Biol 288:1250–1258

    Article  PubMed  CAS  Google Scholar 

  101. Kim HJ, Rice DP, Kettunen PJ, Thesleff I (1998) FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 125:1241–1251

    CAS  PubMed  Google Scholar 

  102. Kim HK, Oxendine I, Kamiya N (2013) High-concentration of BMP2 reduces cell proliferation and increases apoptosis via DKK1 and SOST in human primary periosteal cells. Bone 54:141–150

    Article  CAS  PubMed  Google Scholar 

  103. Kishigami S, Mishina Y (2005) BMP signaling and early embryonic patterning. Cytokine Growth Factor Rev 16:265–278

    Article  CAS  PubMed  Google Scholar 

  104. Klingensmith J, Matsui M, Yang YP, Anderson RM (2010) Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly. Am J Med Genet C Semin Med Genet 154C:43–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Komatsu Y, Yu PB, Kamiya N, Pan H, Fukuda T, Scott GJ, Ray MK, Yamamura K, Mishina Y (2013) Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice. J Bone Miner Res 28:1422–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kouskoura T, El Fersioui Y, Angelini M, Graf D, Katsaros C, Chiquet M (2016) Dislocated tongue muscle attachment and cleft palate formation. J Dent Res 95(4):453–459

    Article  CAS  PubMed  Google Scholar 

  107. Kouskoura T, Fragou N, Alexiou M, John N, Sommer L, Graf D, Katsaros C, Mitsiadis TA (2011) The genetic basis of craniofacial and dental abnormalities. Schweiz Monatsschr Zahnmed 121:636–646

    PubMed  Google Scholar 

  108. Kouskoura T, Kozlova A, Alexiou M, Blumer S, Zouvelou V, Katsaros C, Chiquet M, Mitsiadis TA, Graf D (2013) The etiology of cleft palate formation in BMP7-deficient mice. PLoS One 8:e59463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Krishnan V, Bryant HU, Macdougald OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116:1202–1209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  112. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

    Article  CAS  PubMed  Google Scholar 

  113. Lana-Elola E, Tylzanowski P, Takatalo M, Alakurtti K, Veistinen L, Mitsiadis TA, Graf D, Rice R, Luyten FP, Rice DP (2011) Noggin null allele mice exhibit a microform of holoprosencephaly. Hum Mol Genet 20:4005–4015

    Article  CAS  PubMed  Google Scholar 

  114. Lee MH, Javed A, Kim HJ, Shin HI, Gutierrez S, Choi JY, Rosen V, Stein JL, van Wijnen AJ, Stein GS et al (1999) Transient upregulation of CBFA1 in response to bone morphogenetic protein-2 and transforming growth factor beta1 in C2C12 myogenic cells coincides with suppression of the myogenic phenotype but is not sufficient for osteoblast differentiation. J Cell Biochem 73:114–125

    Article  CAS  PubMed  Google Scholar 

  115. Lehmann K, Seemann P, Silan F, Goecke TO, Irgang S, Kjaer KW, Kjaergaard S, Mahoney MJ, Morlot S, Reissner C et al (2007) A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet 81:388–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lehmann K, Seemann P, Stricker S, Sammar M, Meyer B, Suring K, Majewski F, Tinschert S, Grzeschik KH, Muller D et al (2003) Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proc Natl Acad Sci U S A 100:12277–12282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Li J, Feng J, Liu Y, Ho TV, Grimes W, Ho HA, Park S, Wang S, Chai Y (2015) BMP-SHH signaling network controls epithelial stem cell fate via regulation of its niche in the developing tooth. Dev Cell 33:125–135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M, Morony S, Adamu S, Geng Z, Qiu W et al (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766

    Article  CAS  PubMed  Google Scholar 

  119. Li L, Lin M, Wang Y, Cserjesi P, Chen Z, Chen Y (2011) BmprIa is required in mesenchymal tissue and has limited redundant function with BmprIb in tooth and palate development. Dev Biol 349:451–461

    Article  CAS  PubMed  Google Scholar 

  120. Li S, Meyer NP, Quarto N, Longaker MT (2013) Integration of multiple signaling regulates through apoptosis the differential osteogenic potential of neural crest-derived and mesoderm-derived Osteoblasts. PLoS One 8:e58610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Li S, Quarto N, Longaker MT (2010) Activation of FGF signaling mediates proliferative and osteogenic differences between neural crest derived frontal and mesoderm parietal derived bone. PLoS One 5:e14033

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'Agostin D, Kurahara C, Gao Y, Cao J, Gong J et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869

    Article  PubMed  Google Scholar 

  123. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887

    Article  CAS  PubMed  Google Scholar 

  124. Lim J, Shi Y, Karner CM, Lee SY, Lee WC, He G, Long F (2016) Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in the mouse. Development 143(2):339–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 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  PubMed  Google Scholar 

  126. Liu W, Sun X, Braut A, Mishina Y, Behringer RR, Mina M, Martin JF (2005) Distinct functions for Bmp signaling in lip and palate fusion in mice. Development 132:1453–1461

    Article  CAS  PubMed  Google Scholar 

  127. Liu Z, Tang Y, Qiu T, Cao X, Clemens TL (2006) A dishevelled-1/Smad1 interaction couples WNT and bone morphogenetic protein signaling pathways in uncommitted bone marrow stromal cells. J Biol Chem 281:17156–17163

    Article  CAS  PubMed  Google Scholar 

  128. Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ (2002) Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33:77–80

    Article  CAS  PubMed  Google Scholar 

  129. Lounev VY, Ramachandran R, Wosczyna MN, Yamamoto M, Maidment AD, Shore EM, Glaser DL, Goldhamer DJ, Kaplan FS (2009) Identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am 91:652–663

    Article  PubMed  PubMed Central  Google Scholar 

  130. Lowery JW, Intini G, Gamer L, Lotinun S, Salazar VS, Ote S, Cox K, Baron R, Rosen V (2015) Loss of BMPR2 leads to high bone mass due to increased osteoblast activity. J Cell Sci 128:1308–1315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lu H, Jin Y, Tipoe GL (2000) Alteration in the expression of bone morphogenetic protein-2,3,4,5 mRNA during pathogenesis of cleft palate in BALB/c mice. Arch Oral Biol 45:133–140

    Article  CAS  PubMed  Google Scholar 

  132. 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  PubMed  Google Scholar 

  133. Lydiatt DD, Davis LF (1985) The effects of immobilization on the rabbit temporomandibular joint. J Oral Maxillofac Surg 43:188–193

    Article  CAS  PubMed  Google Scholar 

  134. Lyons KM, Pelton RW, Hogan BL (1990) Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein-2 A (BMP-2 A). Development 109:833–844

    CAS  PubMed  Google Scholar 

  135. Macatee TL, Hammond BP, Arenkiel BR, Francis L, Frank DU, Moon AM (2003) Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development. Development 130:6361–6374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Macias-Silva M, Hoodless PA, Tang SJ, Buchwald M, Wrana JL (1998) Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem 273:25628–25636

    Article  CAS  PubMed  Google Scholar 

  137. Manzanares MC, Goret-Nicaise M, Dhem A (1988) Metopic sutural closure in the human skull. J Anat 161:203–215

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Matsui M, Klingensmith J (2014) Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton. Dev Biol 392:168–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bukulmez H, Balmes G, Krejci P, Mekikian PB, Otani K, Yamaura I et al (2009) FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 18:227–240

    Article  CAS  PubMed  Google Scholar 

  140. Maxson R, Ishii M (2008) The Bmp pathway in skull vault development. Front Oral Biol 12:197–208

    Article  PubMed  Google Scholar 

  141. Mbalaviele G, Sheikh S, Stains JP, Salazar VS, Cheng SL, Chen D, Civitelli R (2005) Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem 94:403–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Miraoui H, Ringe J, Haupl T, Marie PJ (2010) Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Hum Mol Genet 19:1678–1689

    Article  CAS  PubMed  Google Scholar 

  143. Mishina Y, Crombie R, Bradley A, Behringer RR (1999) Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis. Dev Biol 213:314–326

    Article  CAS  PubMed  Google Scholar 

  144. Mishina Y, Snider TN (2014) Neural crest cell signaling pathways critical to cranial bone development and pathology. Exp Cell Res 325:138–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mishina Y, Starbuck MW, Gentile MA, Fukuda T, Kasparcova V, Seedor JG, Hanks MC, Amling M, Pinero GJ, Harada S et al (2004) Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J Biol Chem 279:27560–27566

    Article  CAS  PubMed  Google Scholar 

  146. 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  PubMed  Google Scholar 

  147. Miura S, Singh AP, Mishina Y (2010) Bmpr1a is required for proper migration of the AVE through regulation of Dkk1 expression in the pre-streak mouse embryo. Dev Biol 341:246–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Morikawa Y, Zehir A, Maska E, Deng C, Schneider MD, Mishina Y, Cserjesi P (2009) BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways. Development 136:3575–3584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Morriss-Kay GM, Wilkie AO (2005) Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J Anat 207:637–653

    Article  PubMed  PubMed Central  Google Scholar 

  150. Morvan F, Boulukos K, Clement-Lacroix P, Roman Roman S, Suc-Royer I, Vayssiere B, Ammann P, Martin P, Pinho S, Pognonec P et al (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945

    Article  CAS  PubMed  Google Scholar 

  151. Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, Dorward DW, Glinka A, Grinberg A, Huang SP et al (2001) Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell 1:423–434

    Article  CAS  PubMed  Google Scholar 

  152. Nakashima A, Katagiri T, Tamura M (2005) Cross-talk between Wnt and bone morphogenetic protein 2 (BMP-2) signaling in differentiation pathway of C2C12 myoblasts. J Biol Chem 280:37660–37668

    Article  CAS  PubMed  Google Scholar 

  153. Nakashima T1, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17(10):1231–4. doi: 10.1038/nm.2452

  154. Neskey D, Eloy JA, Casiano RR (2009) Nasal, septal, and turbinate anatomy and embryology. Otolaryngol Clin North Am 42(193–205):vii

    Google Scholar 

  155. Noda K, Mishina Y, Komatsu Y (2016) Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice. Dev Biol 415(2):306–313

    Article  CAS  PubMed  Google Scholar 

  156. Nomura-Kitabayashi A, Phoon CK, Kishigami S, Rosenthal J, Yamauchi Y, Abe K, Yamamura K, Samtani R, Lo CW, Mishina Y (2009) Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest. Am J Physiol Heart Circ Physiol 297:H1617–H1628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Okamoto M, Murai J, Imai Y, Ikegami D, Kamiya N, Kato S, Mishina Y, Yoshikawa H, Tsumaki N (2011) Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. J Bone Miner Res 26:2511–2522

    Article  CAS  PubMed  Google Scholar 

  158. Okamoto M, Murai J, Yoshikawa H, Tsumaki N (2006) Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 21:1022–1033

    Article  CAS  PubMed  Google Scholar 

  159. Otsuka E, Notoya M, Hagiwara H (2003) Treatment of myoblastic C2C12 cells with BMP-2 stimulates vitamin D-induced formation of osteoclasts. Calcif Tissue Int 73:72–77

    Article  CAS  PubMed  Google Scholar 

  160. Pan Q, Yu Y, Chen Q, Li C, Wu H, Wan Y, Ma J, Sun F (2008) Sox9, a key transcription factor of bone morphogenetic protein-2-induced chondrogenesis, is activated through BMP pathway and a CCAAT box in the proximal promoter. J Cell Physiol 217:228–241

    Article  CAS  PubMed  Google Scholar 

  161. Parada C, Chai Y (2015) Mandible and tongue development. Curr Top Dev Biol 115:31–58

    Article  PubMed  PubMed Central  Google Scholar 

  162. Passos-Bueno MR, Serti Eacute AE, Jehee FS, Fanganiello R, Yeh E (2008) Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations. Front Oral Biol 12:107–143

    Article  PubMed  Google Scholar 

  163. Paul S, Lee JC, Yeh LC (2009) A comparative study on BMP-induced osteoclastogenesis and osteoblastogenesis in primary cultures of adult rat bone marrow cells. Growth Factors 27:121–131

    Article  CAS  PubMed  Google Scholar 

  164. Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A 105:20764–20769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Peterson JR, De La Rosa S, Eboda O, Cilwa KE, Agarwal S, Buchman SR, Cederna PS, Xi C, Morris MD, Herndon DN et al (2014) Treatment of heterotopic ossification through remote ATP hydrolysis. Sci Transl Med 6:255ra132

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Phillips FM, Bolt PM, He TC, Haydon RC (2005) Gene therapy for spinal fusion. Spine J 5:250S–258S

    Article  PubMed  Google Scholar 

  167. 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  PubMed  PubMed Central  Google Scholar 

  168. Polinkovsky A, Robin NH, Thomas JT, Irons M, Lynn A, Goodman FR, Reardon W, Kant SG, Brunner HG, van der Burgt I et al (1997) Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nat Genet 17:18–19

    Article  CAS  PubMed  Google Scholar 

  169. Qu S, Tucker SC, Zhao Q, deCrombrugghe B, Wisdom R (1999) Physical and genetic interactions between Alx4 and Cart1. Development 126:359–369

    CAS  PubMed  Google Scholar 

  170. Quarto N, Wan DC, Kwan MD, Panetta NJ, Li S, Longaker MT (2010) Origin matters: differences in embryonic tissue origin and Wnt signaling determine the osteogenic potential and healing capacity of frontal and parietal calvarial bones. J Bone Miner Res 25:1680–1694

    CAS  PubMed  Google Scholar 

  171. 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  PubMed  Google Scholar 

  172. Retting KN, Song B, Yoon BS, Lyons KM (2009) BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 136:1093–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Rice DP, Rice R, Thesleff I (2003) Molecular mechanisms in calvarial bone and suture development, and their relation to craniosynostosis. Eur J Orthod 25:139–148

    Article  PubMed  Google Scholar 

  174. Rigueur D, Brugger S, Anbarchian T, Kim JK, Lee YJ, Lyons K (2015) The type I BMP receptor ACVR1/ALK2 is required for chondrogenesis during development. J Bone Miner Res 30(4):733–741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M (1996) Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357–360

    Article  CAS  PubMed  Google Scholar 

  176. Rountree RB, Schoor M, Chen H, Marks ME, Harley V, Mishina Y, Kingsley DM (2004) BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLoS Biol 2:e355

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Sahar DE, Longaker MT, Quarto N (2005) Sox9 neural crest determinant gene controls patterning and closure of the posterior frontal cranial suture. Dev Biol 280:344–361

    Article  CAS  PubMed  Google Scholar 

  178. Sakata-Goto T, Takahashi K, Kiso H, Huang B, Tsukamoto H, Takemoto M, Hayashi T, Sugai M, Nakamura T, Yokota Y et al (2012) Id2 controls chondrogenesis acting downstream of BMP signaling during maxillary morphogenesis. Bone 50:69–78

    Article  CAS  PubMed  Google Scholar 

  179. 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  PubMed  Google Scholar 

  180. Satokata I, Maas R (1994) Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet 6:348–356

    Article  CAS  PubMed  Google Scholar 

  181. Sedano HO, Cohen MM Jr, Jirasek J, Gorlin RJ (1970) Frontonasal dysplasia. J Pediatr 76:906–913

    Article  CAS  PubMed  Google Scholar 

  182. Seeherman HJ, Li XJ, Bouxsein ML, Wozney JM (2010) rhBMP-2 induces transient bone resorption followed by bone formation in a nonhuman primate core-defect model. J Bone Joint Surg Am 92:411–426

    Article  PubMed  Google Scholar 

  183. Semenov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775

    Article  CAS  PubMed  Google Scholar 

  184. Senarath-Yapa K, Li S, Meyer NP, Longaker MT, Quarto N (2013) Integration of multiple signaling pathways determines differences in the osteogenic potential and tissue regeneration of neural crest-derived and mesoderm-derived calvarial bones. Int J Mol Sci 14:5978–5997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38:525–527

    Article  CAS  PubMed  Google Scholar 

  186. Shukunami C, Ohta Y, Sakuda M, Hiraki Y (1998) Sequential progression of the differentiation program by bone morphogenetic protein-2 in chondrogenic cell line ATDC5. Exp Cell Res 241:1–11

    Article  CAS  PubMed  Google Scholar 

  187. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    Article  CAS  PubMed  Google Scholar 

  188. Simpson AH, Mills L, Noble B (2006) The role of growth factors and related agents in accelerating fracture healing. J Bone Joint Surg Br 88:701–705

    Article  CAS  PubMed  Google Scholar 

  189. Snider TN, Mishina Y (2015) Cranial neural crest cell contribution to craniofacial formation, pathology, and future directions in tissue engineering. Birth Defects Res C Embryo Today 102:324–332

    Article  CAS  Google Scholar 

  190. Solomon BD, Bear KA, Wyllie A, Keaton AA, Dubourg C, David V, Mercier S, Odent S, Hehr U, Paulussen A et al (2012) Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. J Med Genet 49:473–479

    Article  CAS  PubMed  Google Scholar 

  191. Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, Gardner JC, Galas D, Schatzman RC, Beighton P et al (2002) A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 110:144–152

    Article  PubMed  Google Scholar 

  192. Stottmann RW, Choi M, Mishina Y, Meyers EN, Klingensmith J (2004) BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium. Development 131:2205–2218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Stower MJ, Srinivas S (2014) Heading forwards: anterior visceral endoderm migration in patterning the mouse embryo. Philos Trans R Soc Lond B Biol Sci 369:20130546

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Snorradottir S, Center JR et al (2009) New sequence variants associated with bone mineral density. Nat Genet 41:15–17

    Article  CAS  PubMed  Google Scholar 

  195. Sulik KK, Johnston MC (1982) Embryonic origin of holoprosencephaly: interrelationship of the developing brain and face. Scan Electron Microsc (Pt 1):309–322

    Google Scholar 

  196. Tan TY, Kilpatrick N, Farlie PG (2013) Developmental and genetic perspectives on Pierre Robin sequence. Am J Med Genet C Semin Med Genet 163C:295–305

    Article  PubMed  Google Scholar 

  197. Tan X, Weng T, Zhang J, Wang J, Li W, Wan H, Lan Y, Cheng X, Hou N, Liu H et al (2007) Smad4 is required for maintaining normal murine postnatal bone homeostasis. J Cell Sci 120:2162–2170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  199. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349:2483–2494

    Article  CAS  PubMed  Google Scholar 

  200. Trumpp A, Depew MJ, Rubenstein JL, Bishop JM, Martin GR (1999) Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev 13:3136–3148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V (2006) BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 38:1424–1429

    Article  CAS  PubMed  Google Scholar 

  202. Tsumaki N, Nakase T, Miyaji T, Kakiuchi M, Kimura T, Ochi T, Yoshikawa H (2002) Bone morphogenetic protein signals are required for cartilage formation and differently regulate joint development during skeletogenesis. J Bone Miner Res 17:898–906

    Article  CAS  PubMed  Google Scholar 

  203. Twigg SR, Versnel SL, Nurnberg G, Lees MM, Bhat M, Hammond P, Hennekam RC, Hoogeboom AJ, Hurst JA, Johnson D et al (2009) Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. Am J Hum Genet 84:698–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  205. Uz E, Alanay Y, Aktas D, Vargel I, Gucer S, Tuncbilek G, von Eggeling F, Yilmaz E, Deren O, Posorski N et al (2010) Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Am J Hum Genet 86:789–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. van Baardewijk LJ, van der Ende J, Lissenberg-Thunnissen S, Romijn LM, Hawinkels LJ, Sier CF, Schipper IB (2013) Circulating bone morphogenetic protein levels and delayed fracture healing. Int Orthop 37:523–527

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, Quax PH, Vrieling H, Papapoulos SE, ten Dijke P et al (2007) Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 22:19–28

    Article  PubMed  Google Scholar 

  209. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y et al (2003) Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 72:763–771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Wang Y, Zheng Y, Chen D, Chen Y (2013) Enhanced BMP signaling prevents degeneration and leads to endochondral ossification of Meckel's cartilage in mice. Dev Biol 381:301–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT (2003) The BMP antagonist noggin regulates cranial suture fusion. Nature 422:625–629

    Article  CAS  PubMed  Google Scholar 

  212. Warren SM, Greenwald JA, Spector JA, Bouletreau P, Mehrara BJ, Longaker MT (2001) New developments in cranial suture research. Plast Reconstr Surg 107:523–540

    Article  CAS  PubMed  Google Scholar 

  213. Wilkie AO, Morriss-Kay GM (2001) Genetics of craniofacial development and malformation. Nat Rev Genet 2:458–468

    Article  CAS  PubMed  Google Scholar 

  214. 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  PubMed  PubMed Central  Google Scholar 

  215. Winkler DG, Sutherland MS, Ojala E, Turcott E, Geoghegan JC, Shpektor D, Skonier JE, Yu C, Latham JA (2005) Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins. J Biol Chem 280:2498–2502

    Article  CAS  PubMed  Google Scholar 

  216. 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  PubMed  Google Scholar 

  217. Winograd J, Reilly MP, Roe R, Lutz J, Laughner E, Xu X, Hu L, Asakura T, vander Kolk C, Strandberg JD et al (1997) Perinatal lethality and multiple craniofacial malformations in MSX2 transgenic mice. Hum Mol Genet 6:369–379

    Article  CAS  PubMed  Google Scholar 

  218. Wu DT, Bitzer M, Ju W, Mundel P, Bottinger EP (2005) TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J Am Soc Nephrol 16:3211–3221

    Article  CAS  PubMed  Google Scholar 

  219. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17(10):1235–41. doi: 10.1038/nm.2448. PMID: 21909103, PMCID: PMC3192296

  220. Yamaguchi A, Ishizuya T, Kintou N, Wada Y, Katagiri T, Wozney JM, Rosen V, Yoshiki S (1996) Effects of BMP-2, BMP-4, and BMP-6 on osteoblastic differentiation of bone marrow-derived stromal cell lines, ST2 and MC3T3-G2/PA6. Biochem Biophys Res Commun 220:366–371

    Article  CAS  PubMed  Google Scholar 

  221. Yamamoto M, Beppu H, Takaoka K, Meno C, Li E, Miyazono K, Hamada H (2009) Antagonism between Smad1 and Smad2 signaling determines the site of distal visceral endoderm formation in the mouse embryo. J Cell Biol 184:323–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Yamamoto M, Saijoh Y, Perea-Gomez A, Shawlot W, Behringer RR, Ang SL, Hamada H, Meno C (2004) Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature 428:387–392

    Article  CAS  PubMed  Google Scholar 

  223. Yang YP, Anderson RM, Klingensmith J (2010) BMP antagonism protects Nodal signaling in the gastrula to promote the tissue interactions underlying mammalian forebrain and craniofacial patterning. Hum Mol Genet 19:3030–3042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Yang YP, Klingensmith J (2006) Roles of organizer factors and BMP antagonism in mammalian forebrain establishment. Dev Biol 296:458–475

    Article  CAS  PubMed  Google Scholar 

  225. Ye M, Berry-Wynne KM, Asai-Coakwell M, Sundaresan P, Footz T, French CR, Abitbol M, Fleisch VC, Corbett N, Allison WT et al (2010) Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum Mol Genet 19:287–298

    Article  CAS  PubMed  Google Scholar 

  226. Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR et al (2009) High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. J Bone Miner Res 24:2039–2049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci U S A 102:5062–5067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Young B, Minugh-Purvis N, Shimo T, St-Jacques B, Iwamoto M, Enomoto-Iwamoto M, Koyama E, Pacifici M (2006) Indian and sonic hedgehogs regulate synchondrosis growth plate and cranial base development and function. Dev Biol 299:272–282

    Article  CAS  PubMed  Google Scholar 

  229. Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C et al (2008) BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med 14:1363–1369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Yumoto K, Thomas PS, Lane J, Matsuzaki K, Inagaki M, Ninomiya-Tsuji J, Scott GJ, Ray MK, Ishii M, Maxson R et al (2013) TGF-beta-activated kinase 1 (Tak1) mediates agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells. J Biol Chem 288:13467–13480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Zaghloul NA, Brugmann SA (2011) The emerging face of primary cilia. Genesis 49:231–246

    Article  PubMed  PubMed Central  Google Scholar 

  232. Zehentner BK, Dony C, Burtscher H (1999) The transcription factor Sox9 is involved in BMP-2 signaling. J Bone Miner Res 14:1734–1741

    Article  CAS  PubMed  Google Scholar 

  233. 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  PubMed  Google Scholar 

  234. Zhang J, He XC, Tong WG, Johnson T, Wiedemann LM, Mishina Y, Feng JQ, Li L (2006) BMP signaling inhibits hair follicle anagen induction by restricting epithelial stem/progenitor cell activation and expansion. Stem Cells 24(12):2826–2839

    Article  CAS  PubMed  Google Scholar 

  235. Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y (2002) Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 129:4135–4146

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  237. Zouvelou V, Luder HU, Mitsiadis TA, Graf D (2009) Deletion of BMP7 affects the development of bones, teeth, and other ectodermal appendages of the orofacial complex. J Exp Zool B Mol Dev Evol 312B:361–374

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We thank Dr. Sudha Rajderkar for critical reading and Yoshiko Mishina for her artwork. We are sorry for not including all critical references due to the space limitation. Y.M. is supported by the National Institutes of Health (R01DE020843) and the Department of Defense (W81XWH-11-2-0073).

Author information

Authors and Affiliations

  1. University of Michigan, School of Dentistry, Department of Biologic and Materials Sciences, 1011 N. University Avenue, Ann Arbor, MI, 48109-1078, USA

    Yuji Mishina PhD

  2. Department of Sports Medicine, Tenri University, Tenri, Nara, 632-0071, Japan

    Nobuhiro Kamiya MD, PhD

Authors
  1. Yuji Mishina PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nobuhiro Kamiya MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuji Mishina PhD .

Editor information

Editors and Affiliations

  1. School of Medicine, University of Zagreb, Zagreb, Croatia

    Slobodan Vukicevic

  2. perForm Biologics Inc, Holliston, Massachusetts, USA

    Kuber T. Sampath

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Mishina, Y., Kamiya, N. (2017). Embryonic Skeletogenesis and Craniofacial Development. In: Vukicevic, S., Sampath, K. (eds) Bone Morphogenetic Proteins: Systems Biology Regulators. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-47507-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-47507-3_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-47505-9

  • Online ISBN: 978-3-319-47507-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation