CoChat
Sign Up
Cited by 822

The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

BMP signalling in skeletal development, disease and repair

Salazar, Valerie S., Gamer, Laura W., Rosen, Vicki·2016·Nature Reviews Endocrinology
DOI 10.1038/nrendo.2016.12
Open this paper in CoChat — free account

Abstract

Since the identification in 1988 of bone morphogenetic protein 2 (BMP2) as a potent inducer of bone and cartilage formation, BMP superfamily signalling has become one of the most heavily investigated topics in vertebrate skeletal biology. Whereas a large part of this research has focused on the roles of BMP2, BMP4 and BMP7 in the formation and repair of endochondral bone, a large number of BMP superfamily molecules have now been implicated in almost all aspects of bone, cartilage and joint biology. As modulating BMP signalling is currently a major therapeutic target, our rapidly expanding knowledge of how BMP superfamily signalling affects most tissue types of the skeletal system creates enormous potential to translate basic research findings into successful clinical therapies that improve bone mass or quality, ameliorate diseases of skeletal overgrowth, and repair damage to bone and joints. This Review examines the genetic evidence implicating BMP superfamily signalling in vertebrate bone and joint development, discusses a selection of human skeletal disorders associated with altered BMP signalling and summarizes the status of modulating the BMP pathway as a therapeutic target for skeletal trauma and disease.

Overview

Integrity signals

Registry

Crossref · 10.1038/nrendo.2016.12

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 220

  1. Urist, M. R. & Strates, B. S. Bone morphogenetic protein. J. Dent. Res. 50, 1392–1406 (1971). · DOI
  2. Nogami, H. & Urist, M. R. A morphogenetic matrix for differentiation of cartilage in tissue culture. Proc. Soc. Exp. Biol. Med. 134, 530–535 (1970). · DOI
  3. Urist, M. R. Bone: formation by autoinduction. 1965. Clin. Orthop. Relat. Res. 395, 4–10 (2002). Reference 3 shows that post-fetal osteogenesis can be induced in live animals by acelluar decalcified bone fragments and demonstrates the presence of osteoinductive factors in the bone extracellular matrix. · DOI
  4. Wozney, J. M. et al. Novel regulators of bone formation: molecular clones and activities. Science 242, 1528–1534 (1988). · DOI
  5. Lo, K. W., Ulery, B. D., Ashe, K. M. & Laurencin, C. T. Studies of bone morphogenetic protein-based surgical repair. Adv. Drug Deliv. Rev. 64, 1277–1291 (2012). · DOI
  6. Shore, E. M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 38, 525–527 (2006). · DOI
  7. Mizuguchi, T. et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat. Genet. 36, 855–860 (2004). · DOI
  8. Loeys, B. L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37, 275–281 (2005). · DOI
  9. van der Kraan, P. M., Blaney Davidson, E. N. & van den Berg, W. B. Bone morphogenetic proteins and articular cartilage: to serve and protect or a wolf in sheep clothing's? Osteoarthritis Cartilage 18, 735–741 (2010). · DOI
  10. van der Kraan, P. M., Blaney Davidson, E. N. & van den Berg, W. B. A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res. Ther. 12, 201 (2010). · DOI
  11. Johnson, A. B. Operative Therapeusis Vol. 2 Ch. 7 (D. Appleton & Company, 1915).
  12. Huggins, C., Wiseman, S. & Reddi, A. H. Transformation of fibroblasts by allogeneic and xenogeneic transplants of demineralized tooth and bone. J. Exp. Med. 132, 1250–1258 (1970). · DOI
  13. Sampath, T. K. & Reddi, A. H. Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc. Natl Acad. Sci. USA 78, 7599–7603 (1981). · DOI
  14. Sampath, T. K., Muthukumaran, N. & Reddi, A. H. Isolation of osteogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography. Proc. Natl Acad. Sci. USA 84, 7109–7113 (1987). · DOI
  15. Rosen, V. BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev. 20, 475–480 (2009). · DOI
  16. Huminiecki, L. et al. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. BMC Evol. Biol. 9, 28 (2009). · DOI
  17. Tuazon, F. B. & Mullins, M. C. Temporally coordinated signals progressively pattern the anteroposterior and dorsoventral body axes. Semin. Cell Dev. Biol. 42, 118–133 (2015). · DOI
  18. Kahlem, P. & Newfeld, S. J. Informatics approaches to understanding TGFβ pathway regulation. Development 136, 3729–3740 (2009). · DOI
  19. Dereeper, A. et al. Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res. 36, W465–W469 (2008). · DOI · Paper page
  20. Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004). · DOI · Paper page
  21. Schmierer, B. & Hill, C. S. TGFβ–SMAD signal transduction: molecular specificity and functional flexibility. Nat. Rev. Mol. Cell. Biol. 8, 970–982 (2007). Reference 21 provides an in-depth review of fundamental signalling mechanisms of the BMP superfamily. · DOI
  22. Hinck, A. P. Structural studies of the TGF-βs and their receptors — insights into evolution of the TGF-β superfamily. FEBS Lett. 586, 1860–1870 (2012). · DOI
  23. Sampath, T. K., Rashka, K. E., Doctor, J. S., Tucker, R. F. & Hoffmann, F. M. Drosophila transforming growth factor β superfamily proteins induce endochondral bone formation in mammals. Proc. Natl Acad. Sci. USA 90, 6004–6008 (1993). · DOI
  24. Mu, Y., Gudey, S. K. & Landstrom, M. Non-Smad signaling pathways. Cell Tissue Res. 347, 11–20 (2012). · DOI
  25. Ross, S. et al. Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription. EMBO J. 25, 4490–4502 (2006). · DOI
  26. Xi, Q. et al. A poised chromatin platform for TGF-β access to master regulators. Cell 147, 1511–1524 (2011). · DOI
  27. Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 147, 565–576 (2011). · DOI
  28. Trompouki, E. et al. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147, 577–589 (2011). · DOI
  29. Ling, N. et al. Pituitary FSH is released by a heterodimer of the β-subunits from the two forms of inhibin. Nature 321, 779–782 (1986). · DOI
  30. Sporn, M. B. & Todaro, G. J. Autocrine secretion and malignant transformation of cells. N. Engl. J. Med. 303, 878–880 (1980). · DOI
  31. Sun, P. D. & Davies, D. R. The cystine-knot growth-factor superfamily. Annu. Rev. Biophys. Biomol. Struct. 24, 269–291 (1995). · DOI
  32. Gray, A. M. & Mason, A. J. Requirement for activin A and transforming growth factor-β1 pro-regions in homodimer assembly. Science 247, 1328–1330 (1990). · DOI
  33. Ben-Haim, N. et al. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev. Cell 11, 313–323 (2006). · DOI
  34. Shimmi, O., Umulis, D., Othmer, H. & O'Connor, M. B. Facilitated transport of a Dpp/Scw heterodimer by Sog/Tsg leads to robust patterning of the Drosophila blastoderm embryo. Cell 120, 873–886 (2005). · DOI
  35. Egerman, M. A. et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 22, 164–174 (2015). · DOI · Paper page
  36. Smith, S. C. et al. GDF11 does not rescue aging-related pathological hypertrophy. Circ. Res. 117, 926–932 (2015). · DOI
  37. David, L. et al. Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ. Res. 102, 914–922 (2008). · DOI
  38. Greenwald, J. et al. The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol. Cell 11, 605–617 (2003). · DOI
  39. Groppe, J. et al. Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol. Cell 29, 157–168 (2008). · DOI
  40. Lowery, J. W. et al. Loss of BMPR2 leads to high bone mass due to increased osteoblast activity. J. Cell Sci. 128, 1308–1315 (2015). · DOI
  41. Huse, M. et al. The TGF β receptor activation process: an inhibitor- to substrate-binding switch. Mol. Cell 8, 671–682 (2001). · DOI
  42. Newfeld, S. J., Chartoff, E. H., Graff, J. M., Melton, D. A. & Gelbart, W. M. Mothers against dpp encodes a conserved cytoplasmic protein required in DPP/TGF-β responsive cells. Development 122, 2099–2108 (1996). · DOI
  43. Zawel, L. et al. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell 1, 611–617 (1998). · DOI
  44. Shi, Y. et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-β signaling. Cell 94, 585–594 (1998). · DOI
  45. Xiao, Z., Liu, X., Henis, Y. I. & Lodish, H. F. 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 (2000). · DOI
  46. Kim, J., Johnson, K., Chen, H. J., Carroll, S. & Laughon, A. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature 388, 304–308 (1997). · DOI
  47. Lo, R. S., Chen, Y. G., Shi, Y., Pavletich, N. P. & Massague, J. The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-β receptors. EMBO J. 17, 996–1005 (1998). · DOI
  48. Kretzschmar, M., Doody, J. & Massague, J. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389, 618–622 (1997). · DOI
  49. Fuentealba, L. C. et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131, 980–993 (2007). · DOI
  50. Sapkota, G., Alarcon, C., Spagnoli, F. M., Brivanlou, A. H. & Massague, J. Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol. Cell 25, 441–454 (2007). · DOI
  51. Lagna, G., Hata, A., Hemmati-Brivanlou, A. & Massague, J. Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways. Nature 383, 832–836 (1996). · DOI
  52. Moustakas, A. & Heldin, C. H. The regulation of TGFβ signal transduction. Development 136, 3699–3714 (2009). · DOI
  53. Brazil, D. P., Church, R. H., Surae, S., Godson, C. & Martin, F. BMP signalling: agony and antagony in the family. Trends Cell Biol. 25, 249–264 (2015). · DOI
  54. Itoh, S. & ten Dijke, P. Negative regulation of TGF-β receptor/Smad signal transduction. Curr. Opin. Cell Biol. 19, 176–184 (2007). · DOI
  55. Brunet, L. J., McMahon, J. A., McMahon, A. P. & Harland, R. M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280, 1455–1457 (1998). Reference 58 shows that although many BMP superfamily molecules are expressed at developing joints, mice lacking the BMP/GDF antagonist noggin provide the only experimental model known to date with body-wide joint morphogenesis defects, which strongly suggests that BMP signalling must be controlled for joint morphogenesis to occur properly during development. · DOI
  56. Stafford, D. A., Brunet, L. J., Khokha, M. K., Economides, A. N. & Harland, R. M. Cooperative activity of noggin and gremlin 1 in axial skeleton development. Development 138, 1005–1014 (2011). · DOI
  57. Inoue, S. et al. Localization of follistatin, an activin-binding protein, in bone tissues. Calcif. Tissue Int. 55, 395–397 (1994). · DOI
  58. Balemans, W. & Van Hul, W. Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev. Biol. 250, 231–250 (2002). · DOI
  59. Thompson, T. B., Lerch, T. F., Cook, R. W., Woodruff, T. K. & Jardetzky, T. S. The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding. Dev. Cell 9, 535–543 (2005). · DOI
  60. Ge, G., Hopkins, D. R., Ho, W. B. & Greenspan, D. S. GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells. Mol. Cell. Biol. 25, 5846–5858 (2005). · DOI
  61. Kokabu, S. et al. BMP3 suppresses osteoblast differentiation of bone marrow stromal cells via interaction with Acvr2b. Mol. Endocrinol. 26, 87–94 (2012). · DOI
  62. Sakuma, R. et al. Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion. Genes Cells 7, 401–412 (2002). · DOI
  63. Hayashi, H. et al. The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89, 1165–1173 (1997). · DOI
  64. Imamura, T. et al. Smad6 inhibits signalling by the TGF-β superfamily. Nature 389, 622–626 (1997). · DOI
  65. Nakao, A. et al. Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389, 631–635 (1997). · DOI
  66. Murakami, G., Watabe, T., Takaoka, K., Miyazono, K. & Imamura, T. Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol. Biol. Cell 14, 2809–2817 (2003). · DOI
  67. Inoue, Y. & Imamura, T. Regulation of TGF-β family signaling by E3 ubiquitin ligases. Cancer Sci. 99, 2107–2112 (2008). · DOI
  68. Massague, J. TGFβ signalling in context. Nat. Rev. Mol. Cell. Biol. 13, 616–630 (2012). · DOI
  69. Long, F. & Ornitz, D. M. Development of the endochondral skeleton. Cold Spring Harb. Perspect. Biol. 5, a008334 (2013). · DOI
  70. Zeller, R., Lopez-Rios, J. & Zuniga, A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis. Nat. Rev. Genet. 10, 845–858 (2009). · DOI
  71. Logan, M. et al. Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33, 77–80 (2002). · DOI
  72. Zhang, H. & Bradley, A. Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122, 2977–2986 (1996). · DOI
  73. Ovchinnikov, D. A. et al. BMP receptor type IA in limb bud mesenchyme regulates distal outgrowth and patterning. Dev. Biol. 295, 103–115 (2006). · DOI
  74. Lim, J. et al. BMP–Smad4 signaling is required for precartilaginous mesenchymal condensation independent of Sox9 in the mouse. Dev. Biol. 400, 132–138 (2015). Reference 78 shows that canonical BMP signalling is required in the limb mesenchyme for limb bud outgrowth that is mediated by redundant functions of multiple type I BMP receptors and SMAD-4. · DOI
  75. Benazet, J. D. et al. Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds. Development 139, 4250–4260 (2012). · DOI
  76. Bandyopadhyay, A. et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. 2, e216 (2006). Reference 80 shows that BMP2 and BMP4 are essential for bone formation during development. · DOI
  77. Tsuji, K. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat. Genet. 38, 1424–1429 (2006). Reference 81 shows that fracture healing, a repair function of the periosteum, requires progenitor-derived BMP2. · DOI
  78. Tsuji, K. et al. BMP4 is dispensable for skeletogenesis and fracture-healing in the limb. J. Bone Joint Surg. Am. 90 (Suppl. 1), 14–18 (2008). · DOI
  79. Tsuji, K. et al. Conditional deletion of BMP7 from the limb skeleton does not affect bone formation or fracture repair. J. Orthop. Res. 28, 384–389 (2010). · DOI
  80. Settle, S. H. Jr et al. Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev. Biol. 254, 116–130 (2003). · DOI
  81. Storm, E. E. & Kingsley, D. M. Joint patterning defects caused by single and double mutations in members of the bone morphogenetic protein (BMP) family. Development 122, 3969–3979 (1996). · DOI
  82. Pignatti, E., Zeller, R. & Zuniga, A. To BMP or not to BMP during vertebrate limb bud development. Semin. Cell Dev. Biol. 32, 119–127 (2014). · DOI
  83. Sun, X. et al. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Nat. Genet. 25, 83–86 (2000). · DOI
  84. Choi, K. S., Lee, C., Maatouk, D. M. & Harfe, B. D. Bmp2, Bmp4 and Bmp7 are co-required in the mouse AER for normal digit patterning but not limb outgrowth. PLoS ONE 7, e37826 (2012). · DOI
  85. Norrie, J. L. et al. Dynamics of BMP signaling in limb bud mesenchyme and polydactyly. Dev. Biol. 393, 270–281 (2014). · DOI
  86. Reddi, A. H. Cell biology and biochemistry of endochondral bone development. Coll. Relat. Res. 1, 209–226 (1981). · DOI
  87. Cancedda, R., Descalzi Cancedda, F. & Castagnola, P. Chondrocyte differentiation. Int. Rev. Cytol. 159, 265–358 (1995). · DOI
  88. Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663–666 (1996). · DOI
  89. Vortkamp, A. et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613–622 (1996). · DOI
  90. Minina, E., Kreschel, C., Naski, M. C., Ornitz, D. M. & Vortkamp, A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev. Cell 3, 439–449 (2002). · DOI
  91. Cooper, K. L. et al. Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions. Nature 495, 375–378 (2013). · DOI
  92. Galotto, M. et al. Hypertrophic chondrocytes undergo further differentiation to osteoblast-like cells and participate in the initial bone formation in developing chick embryo. J. Bone Miner. Res. 9, 1239–1249 (1994). · DOI
  93. Yang, G. et al. Osteogenic fate of hypertrophic chondrocytes. Cell Res. 24, 1266–1269 (2014). · DOI
  94. Yang, L., Tsang, K. Y., Tang, H. C., Chan, D. & Cheah, K. S. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc. Natl Acad. Sci. USA 111, 12097–12102 (2014). · DOI
  95. Zhou, X. et al. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. 10, e1004820 (2014). · DOI
  96. Ono, N., Ono, W., Nagasawa, T. & Kronenberg, H. M. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat. Cell Biol. 16, 1157–1167 (2014). · DOI
  97. Barna, M. & Niswander, L. Visualization of cartilage formation: insight into cellular properties of skeletal progenitors and chondrodysplasia syndromes. Dev. Cell 12, 931–941 (2007). Reference 101 shows that BMP signalling is necessary for mesenchymal condensation, the first critical step of developmental skeletogenesis. · DOI
  98. Rigueur, D. et al. The type I BMP receptor ACVR1/ALK2 is required for chondrogenesis during development. J. Bone Miner. Res. 30, 733–741 (2015). Reference 102 shows that ALK2, ALK3 and ALK6 mediate BMP signals essential for developmental chondrogenesis. · DOI
  99. Yoon, B. S. et al. Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc. Natl Acad. Sci. USA 102, 5062–5067 (2005). · DOI
  100. Zhang, J. et al. Smad4 is required for the normal organization of the cartilage growth plate. Dev. Biol. 284, 311–322 (2005). · DOI
  101. Retting, K. N., Song, B., Yoon, B. S. & Lyons, K. M. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 136, 1093–1104 (2009). Reference 105 shows that canonical BMP signalling through SMAD1 and SMAD5 drives chondrogenesis and longitudinal bone growth during development. · DOI
  102. Shu, B. et al. BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development. J. Cell Sci. 124, 3428–3440 (2011). · DOI
  103. Merino, R. et al. Expression and function of Gdf-5 during digit skeletogenesis in the embryonic chick leg bud. Dev. Biol. 206, 33–45 (1999). · DOI
  104. Chang, S. C. et al. Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-β superfamily predominantly expressed in long bones during human embryonic development. J. Biol. Chem. 269, 28227–28234 (1994). · DOI
  105. Baur, S. T., Mai, J. J. & Dymecki, S. M. Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development 127, 605–619 (2000). · DOI
  106. Storm, E. E. et al. Limb alterations in brachypodism mice due to mutations in a new member of the TGF β-superfamily. Nature 368, 639–643 (1994). Reference 110 shows that GDF5 is a key ligand required for longitudinal bone growth in the appendicular skeleton. · DOI
  107. Seo, H. S. & Serra, R. Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev. Biol. 310, 304–316 (2007). Reference 111 shows that TGF-β signalling restricts chondrogenesis at developing joint and attenuates chondrocyte maturation in the metaphyseal growth plate. · DOI
  108. Longobardi, L. et al. TGF-β type II receptor/MCP-5 axis: at the crossroad between joint and growth plate development. Dev. Cell 23, 71–81 (2012). Reference 112 shows that joint progenitor cells in the nascent interzone express TGFBR2, PDGF and JAG-1. · DOI
  109. Yang, W. et al. Bmp2 in osteoblasts of periosteum and trabecular bone links bone formation to vascularization and mesenchymal stem cells. J. Cell Sci. 126, 4085–4098 (2013). · DOI
  110. Henry, S. P. et al. Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage. Genesis 47, 805–814 (2009). · DOI
  111. Jing, J. et al. BMP receptor 1A determines the cell fate of the postnatal growth plate. Int. J. Biol. Sci. 9, 895–906 (2013). · DOI
  112. Rodda, S. J. & McMahon, A. P. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133, 3231–3244 (2006). · DOI
  113. Dacquin, R., Starbuck, M., Schinke, T. & Karsenty, G. Mouse α1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast. Dev. Dyn. 224, 245–251 (2002). · DOI
  114. Liu, F. et al. Expression and activity of osteoblast-targeted Cre recombinase transgenes in murine skeletal tissues. Int. J. Dev. Biol. 48, 645–653 (2004). · DOI
  115. Maes, C., Kobayashi, T. & Kronenberg, H. M. A novel transgenic mouse model to study the osteoblast lineage in vivo. Ann. NY Acad. Sci. 1116, 149–164 (2007). · DOI
  116. Salazar, V. S. et al. Embryonic ablation of osteoblast Smad4 interrupts matrix synthesis in response to canonical Wnt signaling and causes an osteogenesis-imperfecta-like phenotype. J. Cell Sci. 126, 4974–4984 (2013). · DOI
  117. Tan, X. et al. Smad4 is required for maintaining normal murine postnatal bone homeostasis. J. Cell Sci. 120, 2162–2170 (2007). · DOI
  118. McBride, S. H. et al. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells. PLoS ONE 9, e96862 (2014). · DOI
  119. Feng, J. et al. Abnormalities in the enamel in Bmp2-deficient mice. Cells Tissues Organs 194, 216–221 (2011). · DOI
  120. Guo, F. et al. Bmp2 deletion causes an amelogenesis imperfecta phenotype via regulating enamel gene expression. J. Cell. Physiol. 230, 1871–1882 (2014). · DOI
  121. McBride-Gagyi, S. H., McKenzie, J. A., Buettmann, E. G., Gardner, M. J. & Silva, M. J. Bmp2 conditional knockout in osteoblasts and endothelial cells does not impair bone formation after injury or mechanical loading in adult mice. Bone 81, 533–543 (2015). · DOI
  122. Chappuis, V. et al. Periosteal BMP2 activity drives bone graft healing. Bone 51, 800–809 (2012). · DOI
  123. Mi, M. et al. Chondrocyte BMP2 signaling plays an essential role in bone fracture healing. Gene 512, 211–218 (2013). · DOI
  124. Sanchez-Duffhues, G., Hiepen, C., Knaus, P. & Ten Dijke, P. Bone morphogenetic protein signaling in bone homeostasis. Bone 80, 43–59 (2015). · DOI
  125. Mishina, Y. et al. Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J. Biol. Chem. 279, 27560–27566 (2004). · DOI
  126. Ray, A., Singh, P. N., Sohaskey, M. L., Harland, R. M. & Bandyopadhyay, A. Precise spatial restriction of BMP signaling is essential for articular cartilage differentiation. Development 142, 1169–1179 (2015). · DOI
  127. Mitrovic, D. R. Development of the metatarsophalangeal joint of the chick embryo: morphological, ultrastructural and histochemical studies. Am. J. Anat. 150, 333–347 (1977). · DOI
  128. Wolfman, N. M. et al. 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 (1997). Reference 132 shows that GDF ligands induce secondary joint structures including tendon and ligament. · DOI
  129. Li, T. et al. Joint TGF-β type II receptor-expressing cells: ontogeny and characterization as joint progenitors. Stem Cells Dev. 22, 1342–1359 (2013). · DOI
  130. Spagnoli, A. et al. TGF-β signaling is essential for joint morphogenesis. J. Cell Biol. 177, 1105–1117 (2007). · DOI
  131. Dyment, N. A. et al. Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis. Dev. Biol. 405, 96–107 (2015). · DOI
  132. Koyama, E. et al. A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. Dev. Biol. 316, 62–73 (2008). Reference 136 shows that cells expressing Gdf5 during development populate most structures in the synovial joint. · DOI
  133. Rountree, R. B. et al. BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLoS Biol. 2, e355 (2004). Reference 137 shows that BMPR1A is dispensable in the Gdf5+ interzone for synovial joint morphogenesis. · DOI
  134. Zimmerman, L. B., De Jesus-Escobar, J. M. & Harland, R. M. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86, 599–606 (1996). · DOI
  135. Nishitoh, H. et al. Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. J. Biol. Chem. 271, 21345–21352 (1996). · DOI
  136. Nickel, J., Kotzsch, A., Sebald, W. & Mueller, T. D. A single residue of GDF-5 defines binding specificity to BMP receptor IB. J. Mol. Biol. 349, 933–947 (2005). Reference 140 shows that GDF5 signalling is highly dependent on BMPR1B (ALK6), consistent with the observation that mice lacking GDF5, BMPR1B, or both GDF5 and BMPR1B have strikingly similar skeletal phenotypes. · DOI
  137. Kotzsch, A., Nickel, J., Sebald, W. & Mueller, T. D. Purification, crystallization and preliminary data analysis of ligand-receptor complexes of growth and differentiation factor 5 (GDF5) and BMP receptor IB (BRIB). Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 65, 779–783 (2009). · DOI
  138. Gong, Y. et al. Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat. Genet. 21, 302–304 (1999). · DOI
  139. Seemann, P. et al. Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN. PLoS Genet. 5, e1000747 (2009). · DOI
  140. Yi, S. E., Daluiski, A., Pederson, R., Rosen, V. & Lyons, K. M. The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 127, 621–630 (2000). · DOI
  141. Wu, L. et al. Human developmental chondrogenesis as a basis for engineering chondrocytes from pluripotent stem cells. Stem Cell Rep. 1, 575–589 (2013). · DOI
  142. Rosen, V. et al. Responsiveness of clonal limb bud cell lines to bone morphogenetic protein 2 reveals a sequential relationship between cartilage and bone cell phenotypes. J. Bone Miner. Res. 9, 1759–1768 (1994). · DOI
  143. Larsson, J. et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-β type I receptor-deficient mice. EMBO J. 20, 1663–1673 (2001). · DOI · Paper page
  144. Oshima, M., Oshima, H. & Taketo, M. M. TGF-β receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev. Biol. 179, 297–302 (1996). · DOI
  145. Baffi, M. O. et al. Conditional deletion of the TGF-β type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Dev. Biol. 276, 124–142 (2004). · DOI
  146. Eyal, S. et al. On the development of the patella. Development 142, 1831–1839 (2015). · DOI
  147. Rasmussen, S. A. et al. Epidemiology of osteochondrodysplasias: changing trends due to advances in prenatal diagnosis. Am. J. Med. Genet. 61, 49–58 (1996). · DOI
  148. Weldner, B. M., Persson, P. H. & Ivarsson, S. A. Prenatal diagnosis of dwarfism by ultrasound screening. Arch. Dis. Child. 60, 1070–1072 (1985). · DOI
  149. MacCarrick, G. et al. Loeys–Dietz syndrome: a primer for diagnosis and management. Genet. Med. 16, 576–587 (2014). · DOI
  150. Regalado, E. S. et al. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ. Res. 109, 680–686 (2011). · DOI
  151. Kinoshita, A. et al. Domain-specific mutations in TGFB1 result in Camurati–Engelmann disease. Nat. Genet. 26, 19–20 (2000). · DOI
  152. Ghadami, M. et al. Genetic mapping of the Camurati–Engelmann disease locus to chromosome 19q13.1–q13.3. Am. J. Hum. Genet. 66, 143–147 (2000). · DOI
  153. Campos-Xavier, B. et al. Phenotypic variability at the TGF-β1 locus in Camurati–Engelmann disease. Hum. Genet. 109, 653–658 (2001). · DOI
  154. Waning, D. L. et al. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat. Med. 21, 1262–1271 (2015). · DOI
  155. Smaldone, S. et al. Fibrillin-1 regulates skeletal stem cell differentiation by modulating TGFβ activity within the marrow niche. J. Bone Miner. Res. 31, 86–97 (2015). · DOI
  156. Grafe, I. et al. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat. Med. 20, 670–675 (2014). · DOI
  157. Hellmann, T. V., Nickel, J. & Mueller, T. D. in Mutations in Human Genetic Disease (eds Cooper, D. N. & Chen, J. M.) 11–54 (Intech Publishing, 2012). Reference 162 provides a summary of GDF5 mutations associated with human skeletal disorders.
  158. Douzgou, S., Lehmann, K., Mingarelli, R., Mundlos, S. & Dallapiccola, B. Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia. Am. J. Med. Genet. A 146A, 2116–2121 (2008). · DOI
  159. Faiyaz-Ul-Haque, M. et al. Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). Clin. Genet. 61, 454–458 (2002). · DOI
  160. Du Pan, C. M. Absence congenitale du perone sans deformation du tibia: curieuses deformations congenitales des mains. Revue d'Orthopedie 11, 227–234 (in French) (1924).
  161. Grebe, H. Chondrodysplasia; Monographie (Edizioni dell'Istituto Gregorio Mendel, 1955).
  162. Hunter, A. G. & Thompson, M. W. Acromesomelic dwarfism: description of a patient and comparison with previously reported cases. Hum. Genet. 34, 107–113 (1976). · DOI
  163. Thomas, J. T. et al. A human chondrodysplasia due to a mutation in a TGF-β superfamily member. Nat. Genet. 12, 315–317 (1996). · DOI
  164. Thomas, J. T. et al. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat. Genet. 17, 58–64 (1997). · DOI
  165. Graul-Neumann, L. M. et al. Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe. Eur. J. Hum. Genet. 22, 726–733 (2014). · DOI
  166. Costa, T. et al. Grebe syndrome: clinical and radiographic findings in affected individuals and heterozygous carriers. Am. J. Med. Genet. 75, 523–529 (1998). · DOI
  167. Demirhan, O. et al. A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies. J. Med. Genet. 42, 314–317 (2005). · DOI
  168. Seemann, P. et al. Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J. Clin. Invest. 115, 2373–2381 (2005). · DOI
  169. Lehmann, K. et al. Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proc. Natl Acad. Sci. USA 100, 12277–12282 (2003). · DOI
  170. Kjaer, K. W. et al. A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2. J. Med. Genet. 43, 225–231 (2006). · DOI
  171. Robin, N. H., Gunay-Aygun, M., Polinkovsky, A., Warman, M. L. & Morrison, S. Clinical and locus heterogeneity in brachydactyly type C. Am. J. Med. Genet. 68, 369–377 (1997). · DOI
  172. Polinkovsky, A. et al. Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nat. Genet. 17, 18–19 (1997). · DOI
  173. Polymeropoulos, M. H., Ide, S. E., Magyari, T. & Francomano, C. A. Brachydactyly type C gene maps to human chromsome 12q24. Genomics 38, 45–50 (1996). · DOI
  174. Savarirayan, R. et al. Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families. Am. J. Med. Genet. A 117A, 136–142 (2003). · DOI
  175. Le Goff, C., Michot, C. & Cormier-Daire, V. Myhre syndrome. Clin. Genet. 85, 503–513 (2014). · DOI
  176. Starr, L. J. et al. Myhre syndrome: clinical features and restrictive cardiopulmonary complications. Am. J. Med. Genet. A 167A, 2893–2901 (2015). · DOI
  177. Le Goff, C. et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat. Genet. 44, 85–88 (2012). · DOI
  178. Minina, E. et al. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 128, 4523–4534 (2001). Reference 183 shows that longitudinal bone growth in the appendicular skeleton is coordinated by BMP signals as well as other critical forms of molecular crosstalk between distinct cell types in the developing growth plate. · DOI
  179. Freire-Maia, N., Maia, N. A. & Pacheco, C. N. Mohr-Wriedt (A2) brachydactyly: analysis of a large Brazilian kindred. Hum. Hered. 30, 225–231 (1980). · DOI
  180. Dathe, K. et al. Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am. J. Hum. Genet. 84, 483–492 (2009). · DOI
  181. Lehmann, K. et al. 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 (2007). · DOI
  182. Pang, X. et al. A novel missense mutation of NOG interferes with the dimerization of NOG and causes proximal symphalangism syndrome in a Chinese family. Ann. Otol. Rhinol. Laryngol. 124, 745–751 (2015). · DOI
  183. Masuda, S. et al. A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss. Biochem. Biophys. Res. Commun. 447, 496–502 (2014). · DOI
  184. Takahashi, T. et al. Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin. Genet. 60, 447–451 (2001). · DOI
  185. Brown, D. J. et al. Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am. J. Hum. Genet. 71, 618–624 (2002). · DOI
  186. Dawson, K. et al. GDF5 is a second locus for multiple-synostosis syndrome. Am. J. Hum. Genet. 78, 708–712 (2006). · DOI
  187. Ye, M. et al. Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum. Mol. Genet. 19, 287–298 (2010). · DOI
  188. Levine, A. J., Levine, Z. J. & Brivanlou, A. H. GDF3 is a BMP inhibitor that can activate Nodal signaling only at very high doses. Dev. Biol. 325, 43–48 (2009). · DOI
  189. Huning, I. & Gillessen-Kaesbach, G. Fibrodysplasia ossificans progressiva: clinical course, genetic mutations and genotype–phenotype correlation. Mol. Syndromol. 5, 201–211 (2014). · DOI
  190. Kaplan, F. S. et al. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J. Bone Joint Surg. Am. 92, 686–691 (2010). · DOI
  191. Zhou, X. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531–543 (2010). · DOI
  192. Rajkovic, Z. & Krklec, V. The oldest treated bone fracture in Croatia — 130,000 years ago [Croatian]. Acta Med. Croat. 62, 89–92 (2008).
  193. Erfan Zaki, M. Success of long bone fracture healing in ancient Egypt: a paleoepidemiological study of the Giza Necropolis skeletons. Acta Med. Hist. Adriat. 11, 275–284 (2013).
  194. Redfern, R. A regional examination of surgery and fracture treatment in Iron Age and Roman Britain. Int. J. Osteoarchaeol. 20, 443–471 (2010). · DOI
  195. Anne, J. et al. Synchrotron imaging reveals bone healing and remodelling strategies in extinct and extant vertebrates. J. R. Soc. Interface 11, 20140277 (2014). · DOI
  196. Gautschi, O. P., Frey, S. P. & Zellweger, R. Bone morphogenetic proteins in clinical applications. ANZ J. Surg. 77, 626–631 (2007). · DOI
  197. Ali, I. H. & Brazil, D. P. Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. Br. J. Pharmacol. 171, 3620–3632 (2014). Reference 203 provides a recent summary of successes and challenges using BMPs in the clinic. · DOI
  198. Wheeler, D. L. & Enneking, W. F. Allograft bone decreases in strength in vivo over time. Clin. Orthop. Relat. Res. 435, 36–42 (2005). · DOI
  199. Colnot, C. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J. Bone Miner. Res. 24, 274–282 (2009). · DOI
  200. Tiyapatanaputi, P. et al. A novel murine segmental femoral graft model. J. Orthop. Res. 22, 1254–1260 (2004). · DOI

200 of 220 shown

Cited by

Sorted by citations

Metadata

Authors
Salazar, V. S., Gamer, L. W., & Rosen, V.
Venue
Nature Reviews Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2016-02-19
Volume
12
Issue
4
Pages
203-221
ISSN
  • 1759-5029
  • 1759-5037
DOI
10.1038/nrendo.2016.12
Cited by
822
References
6
Language
en
Licence
www.springer.com/tdm (tdm)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review