A pathway to bone: Signaling molecules and transcription factors involved in chondrocyte development and maturation

Development (Cambridge)

Volumn 142, Issue 5, 2015, Pages 817-831

  Kozhemyakina, Elena ^a   Lassar, Andrew B ^a   Zelzer, Elazar ^b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b WEIZMANN INSTITUTE OF SCIENCE   (Israel)

Author keywords

Chondrocyte hypertrophy; Chondrogenesis; Fgfr3; Growth plate; Ihh; PTHrP; Sox9

Indexed keywords

BONE MORPHOGENETIC PROTEIN; CYCLIC AMP DEPENDENT PROTEIN KINASE; EPIDERMAL GROWTH FACTOR RECEPTOR; FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR RECEPTOR 3; HYPOXIA INDUCIBLE FACTOR 1ALPHA; MYOCYTE ENHANCER FACTOR 2; SOMATOMEDIN C; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FOXA; TRANSCRIPTION FACTOR SOX9; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; WNT PROTEIN;

ARTICLE; CARTILAGE CELL; CELL DIFFERENTIATION; CELL MATURATION; CELL STRUCTURE; CHONDROGENESIS; GROWTH PLATE; HUMAN; HYPERTROPHY; LEG LENGTHENING; LIMB BUD; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; WNT SIGNALING PATHWAY; ANIMAL; CYTOLOGY; GENETICS; METABOLISM; PHYSIOLOGY;

ANIMALS; CHONDROCYTES; CHONDROGENESIS; GROWTH PLATE; HUMANS; TRANSCRIPTION FACTORS;

EID: 84923281302     PISSN: 09501991     EISSN: 14779129     Source Type: Journal    
DOI: 10.1242/dev.105536     Document Type: Article

References (201)

1. Ahrens, P. B., Solursh, M. and Reiter, R. S. (1977). Stage-related capacity for limb chondrogenesis in cell culture. Dev. Biol. 60, 69-82.
2. Akiyama, H., Chaboissier, M.-C., Martin, J.F., Schedl, A. and DeCrombrugghe, B. (2002). The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 16, 2813-2828.
3. Akiyama, H., Lyons, J. P., Mori-Akiyama, Y., Yang, X., Zhang, R., Zhang, Z., Deng, J. M., Taketo, M. M., Nakamura, T., Behringer, R. R. et al. (2004). Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 18, 1072-1087.
4. Amarilio, R., Viukov, S. V., Sharir, A., Eshkar-Oren, I., Johnson, R. S. and Zelzer, E. (2007). HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Development 134, 3917-3928.
5. Arnold, M. A., Kim, Y., Czubryt, M. P., Phan, D., McAnally, J., Qi, X., Shelton, J. M., Richardson, J. A., Bassel-Duby, R. and Olson, E. N. (2007). MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev. Cell 12, 377-389.
6. Bae, Y. S., Kang, S.W., Seo, M. S., Baines, I. C., Tekle, E., Chock, P. B. and Rhee, S. G. (1997). Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J. Biol. Chem. 272, 217-221.
7. Barna, M. and Niswander, L. (2007). Visualization of cartilage formation: insight into cellular properties of skeletal progenitors and chondrodysplasia syndromes. Dev. Cell 12, 931-941.
8. Bell, D. M., Leung, K. K. H., Wheatley, S. C., Ng, L. J., Zhou, S., Ling, K. W., Sham, M. H., Koopman, P., Tam, P. P. L. and Cheah, K. S. E. (1997). SOX9 directly regulates the type-II collagen gene. Nat. Genet. 16, 174-178.
9. Bentovim, L., Amarilio, R. and Zelzer, E. (2012). HIF1alpha is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development. Development 139, 4473-4483.
10. Benya, P. D. and Shaffer, J. D. (1982). Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30, 215-224.
11. Berdeaux, R., Goebel, N., Banaszynski, L., Takemori, H., Wandless, T., Shelton, G. D. and Montminy, M. (2007). SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nat. Med. 13, 597-603.
12. Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R. and de Crombrugghe, B. (1999). Sox9 is required for cartilage formation. Nat. Genet. 22, 85-89.
13. Bi, W., Huang, W., Whitworth, D. J., Deng, J. M., Zhang, Z., Behringer, R. R. and de Crombrugghe, B. (2001). Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc. Natl. Acad. Sci. USA 98, 6698-6703.
14. Blitz, E., Viukov, S., Sharir, A., Shwartz, Y., Galloway, J. L., Price, B. A., Johnson, R. L., Tabin, C. J., Schweitzer, R. and Zelzer, E. (2009). Bone ridgepatterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junction. Dev. Cell 17, 861-873.
15. Blitz, E., Sharir, A., Akiyama, H. and Zelzer, E. (2013). Tendon-bone attachment unit is formed modularly by a distinct pool of Scx- and Sox9-positive progenitors. Development 140, 2680-2690.
16. Bonaventure, J., Kadhom, N., Cohen-Solal, L., Ng, K. H., Bourguignon, J., Lasselin, C. and Freisinger, P. (1994). Reexpression of cartilage-specific genes by dedifferentiated human articular chondrocytes cultured in alginate beads. Exp. Cell Res. 212, 97-104.
17. Borjesson, A. E., Windahl, S. H., Karimian, E., Eriksson, E. E., Lagerquist, M. K., Engdahl, C., Antal, M. C., Krust, A., Chambon, P., Savendahl, L. et al. (2012). The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice. Am. J. Physiol. Endocrinol. Metab. 302, E1381-E1389.
18. Capdevila, J. and Johnson, R. L. (1998). Endogenous and ectopic expression of noggin suggests a conserved mechanism for regulation of BMP function during limb and somite patterning. Dev. Biol. 197, 205-217.
19. Carrington, J. L., Chen, P., Yanagishita, M. and Reddi, A. H. (1991). Osteogenin (bone morphogenetic protein-3) stimulates cartilage formation by chick limb bud cells in vitro. Dev. Biol. 146, 406-415.
20. Chen, L., Adar, R., Yang, X., Monsonego, E. O., Li, C., Hauschka, P. V., Yayon, A. and Deng, C.-X. (1999). Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J. Clin. Invest. 104, 1517-1525.
21. Chiang, C., Litingtung, Y., Lee, E., Young, K. E., Corden, J. L., Westphal, H. and Beachy, P. A. (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407-413.
22. Chimal-Monroy, J. and Diaz de Leon, L. (1997). Differential effects of transforming growth factors beta 1, beta 2, beta 3 and beta 5 on chondrogenesis in mouse limb bud mesenchymal cells. Int. J. Dev. Biol. 41, 91-102.
23. Chusho, H., Tamura, N., Ogawa, Y., Yasoda, A., Suda, M., Miyazawa, T., Nakamura, K., Nakao, K., Kurihara, T., Komatsu, Y. et al. (2001). Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc. Natl. Acad. Sci. USA 98, 4016-4021.
24. Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G. and Ornitz, D. M. (1996). Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat. Genet. 12, 390-397.
25. Cooper, K. L., Oh, S., Sung, Y., Dasari, R. R., Kirschner, M. W. and Tabin, C. J. (2013). Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions. Nature 495, 375-378.
26. Correa, D., Hesse, E., Seriwatanachai, D., Kiviranta, R., Saito, H., Yamana, K., Neff, L., Atfi, A., Coillard, L., Sitara, D. et al. (2010). Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes. Dev. Cell 19, 533-546.
27. Daoud, G., Kempf, H., Kumar, D., Kozhemyakina, E., Holowacz, T., Kim, D.-W., Ionescu, A. and Lassar, A. B. (2014). BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH. Development 141, 3978-3987.
28. Day, T. F., Guo, X., Garrett-Beal, L. and Yang, Y. (2005). Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739-750.
29. de Crombrugghe, B., Lefebvre, V. and Nakashima, K. (2001). Regulatory mechanisms in the pathways of cartilage and bone formation. Curr. Opin. Cell Biol. 13, 721-728.
30. de Frutos, C. A., Vega, S., Manzanares, M., Flores, J. M., Huertas, H., Martıìnez-Frıìas, M. L. and Nieto, M. A. (2007). Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias. Dev. Cell 13, 872-883.
31. Degnin, C. R., Laederich, M. B. and Horton, W. A. (2010). FGFs in endochondral skeletal development. J. Cell Biochem. 110, 1046-1057.
32. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. and Leder, P. (1996). Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911-921.
33. Dong, Y.-F., Soung, D. Y., Schwarz, E. M., O’Keefe, R. J. and Drissi, H. (2006). Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J. Cell Physiol. 208, 77-86.
34. Drissi, M. H., Li, X., Sheu, T. J., Zuscik, M. J., Schwarz, E. M., Puzas, J. E., Rosier, R. N. and O’Keefe, R. J. (2003). Runx2/Cbfa1 stimulation by retinoic acid is potentiated by BMP2 signaling through interaction with Smad1 on the collagen X promoter in chondrocytes. J. Cell Biochem. 90, 1287-1298.
35. Dudley, A. T., Ros, M. A. and Tabin, C. J. (2002). A re-examination of proximodistal patterning during vertebrate limb development. Nature 418, 539-544.
36. Duprez, D., Bell, E. J. d. H., Richardson, M. K., Archer, C. W., Wolpert, L., Brickell, P. M. and Francis-West, P. H. (1996). Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb. Mech. Dev. 57, 145-157.
37. Dy, P., Wang, W., Bhattaram, P., Wang, Q., Wang, L., Ballock, R. T. and Lefebvre, V. (2012). Sox9 directs hypertrophicmaturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev. Cell 22, 597-609.
38. Enomoto, H., Enomoto-Iwamoto, M., Iwamoto, M., Nomura, S., Himeno, M., Kitamura, Y., Kishimoto, T. and Komori, T. (2000). Cbfa1 is a positive regulatory factor in chondrocyte maturation. J. Biol. Chem. 275, 8695-8702.
39. Enomoto-Iwamoto, M., Kitagaki, J., Koyama, E., Tamamura, Y., Wu, C., Kanatani, N., Koike, T., Okada, H., Komori, T., Yoneda, T. et al. (2002). The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. Dev. Biol. 251, 142-156.
40. Fallon, J. F., Lopez, A., Ros, M. A., Savage, M. P., Olwin, B. B. and Simandl, B. K. (1994). FGF-2: apical ectodermal ridge growth signal for chick limb development. Science 264, 104-107.
41. Fan, C., Katsuyama, M., Nishinaka, T. and Yabe-Nishimura, C. (2005). Transactivation of the EGF receptor and a PI3 kinase-ATF-1 pathway is involved in the upregulation of NOX1, a catalytic subunit of NADPH oxidase. FEBS Lett. 579, 1301-1305.
42. Fisher, M. C., Clinton, G. M., Maihle, N. J. and Dealy, C. N. (2007). Requirement for ErbB2/ErbB signaling in developing cartilage and bone. Dev. Growth Differ. 49, 503-513.
43. Foldynova-Trantirkova, S., Wilcox, W. R. and Krejci, P. (2012). Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum. Mutat. 33, 29-41.
44. Furumatsu, T., Tsuda, M., Taniguchi, N., Tajima, Y. and Asahara, H. (2005). Smad3 induces chondrogenesis through the activation of SOX9 via CREBbinding protein/p300 recruitment. J. Biol. Chem. 280, 8343-8350.
45. Gao, B. and Yang, Y. (2013). Planar cell polarity in vertebrate limb morphogenesis. Curr. Opin. Genet. Dev. 23, 438-444.
46. Germiller, J. A. and Goldstein, S. A. (1997). Structure and function of embryonic growth plate in the absence of functioning skeletal muscle. J. Orthop. Res. 15, 362-370.
47. Gibson, G. (1998). Active role of chondrocyte apoptosis in endochondral ossification. Microsc. Res. Tech. 43, 191-204.
48. Grozinger, C. M. and Schreiber, S. L. (2000). Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc. Natl. Acad. Sci. USA 97, 7835-7840.
49. Guo, J., Chung, U.-I., Kondo, H., Bringhurst, F. R. and Kronenberg, H.M. (2002). The PTH/PTHrP receptor can delay chondrocyte hypertrophy in vivo without activating phospholipase C. Dev. Cell 3, 183-194.
50. Hall, B. K. and Miyake, T. (1992). The membranous skeleton: the role of cell condensations in vertebrate skeletogenesis. Anat. Embryol. (Berl.) 186, 107-124.
51. Hamburger, V. and Waugh, M. (1940). The primary development of the skeleton in nerveless and poorly innervated limb transplants of chick embryos. Phsiol. Zool. 13, 367-384.
52. Hanai, J.-i., Chen, L. F., Kanno, T., Ohtani-Fujita, N., Kim, W. Y., Guo, W.-H., Imamura, T., Ishidou, Y., Fukuchi, M., Shi, M.-J. et al. (1999). Interaction and functional cooperation of PEBP2/CBF with Smads: synergistic induction of the immunoglobulin germline Calpha promoter. J. Biol. Chem. 274, 31577-31582.
53. Hartmann, C. and Tabin, C. J. (2000). Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 127, 3141-3159.
54. Hattori, T., Muller, C., Gebhard, S., Bauer, E., Pausch, F., Schlund, B., Bosl, M. R., Hess, A., Surmann-Schmitt, C., von der Mark, H. et al. (2010). SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification. Development 137, 901-911.
55. Hill, T. P., Spater, D., Taketo, M. M., Birchmeier, W. and Hartmann, C. (2005). Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev. Cell 8, 727-738.
56. Hilton, M. J., Tu, X., Cook, J., Hu, H. and Long, F. (2005). Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Development 132, 4339-4351.
57. Hosseini, A. and Hogg, D. A. (1991). The effects of paralysis on skeletal development in the chick embryo. II. Effects on histogenesis of the tibia. J. Anat. 177, 169-178.
58. Huang, W., Zhou, X., Lefebvre, V. and de Crombrugghe, B. (2000). Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9’s ability to transactivate a Col2a1 chondrocyte-specific enhancer. Mol. Cell. Biol. 20, 4149-4158.
59. Hung, I. H., Yu, K., Lavine, K. J. and Ornitz, D. M. (2007). FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev. Biol. 307, 300-313.
60. Ikegami, D., Akiyama, H., Suzuki, A., Nakamura, T., Nakano, T., Yoshikawa, H. and Tsumaki, N. (2011). Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development 138, 1507-1519.
61. Inada, M., Yasui, T., Nomura, S., Miyake, S., Deguchi, K., Himeno, M., Sato, M., Yamagiwa, H., Kimura, T., Yasui, N. et al. (1999). Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev. Dyn. 214, 279-290.
62. Inada, M., Wang, Y., Byrne, M. H., Rahman, M. U., Miyaura, C., Lopez-Otin, C. and Krane, S. M. (2004). Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc. Natl. Acad. Sci. USA 101, 17192-17197.
63. Ionescu, A., Kozhemyakina, E., Nicolae, C., Kaestner, K. H., Olsen, B. R. and Lassar, A. B. (2012). FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program. Dev. Cell 22, 927-939.
64. Iwata, T., Chen, L., Li, C.-L., Ovchinnikov, D. A., Behringer, R. R., Francomano, C. A. and Deng, C.-X. (2000). A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. Hum. Mol. Genet. 9, 1603-1613.
65. Iwata, T., Li, C.-L., Deng, C.-X. and Francomano, C. A. (2001). Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. Hum. Mol. Genet. 10, 1255-1264.
66. Jacob, A. L., Smith, C., Partanen, J. and Ornitz, D. M. (2006). Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev. Biol. 296, 315-328.
67. Javed, A., Bae, J.-S., Afzal, F., Gutierrez, S., Pratap, J., Zaidi, S. K., Lou, Y., van Wijnen, A. J., Stein, J. L., Stein, G. S. et al. (2008). Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal. J. Biol. Chem. 283, 8412-8422.
68. Kaestner, K. H., Hiemisch, H. and Schutz, G. (1998). Targeted disruption of the gene encoding hepatocyte nuclear factor 3gamma results in reduced transcription of hepatocyte-specific genes. Mol. Cell. Biol. 18, 4245-4251.
69. Karamboulas, K., Dranse, H. J. and Underhill, T. M. (2010). Regulation of BMPdependent chondrogenesis in early limb mesenchyme by TGFbeta signals. J. Cell Sci. 123, 2068-2076.
70. Karaplis, A. C., Luz, A., Glowacki, J., Bronson, R. T., Tybulewicz, V. L., Kronenberg, H. M. and Mulligan, R. C. (1994). Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8, 277-289.
71. Karp, S. J., Schipani, E., St-Jacques, B., Hunzelman, J., Kronenberg, H. and McMahon, A. P. (2000). Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development 127, 543-548.
72. Kato, N. and Aoyama, H. (1998). Dermomyotomal origin of the ribs as revealed by extirpation and transplantation experiments in chick and quail embryos. Development 125, 3437-3443.
73. Kawakami, Y., Ishikawa, T., Shimabara, M., Tanda, N., Enomoto-Iwamoto, M., Iwamoto, M., Kuwana, T., Ueki, A., Noji, S. and Nohno, T. (1996). BMP signaling during bone pattern determination in the developing limb. Development 122, 3557-3566.
74. Kempf, H., Ionescu, A., Udager, A. M. and Lassar, A. B. (2007). Prochondrogenic signals induce a competence for Runx2 to activate hypertrophic chondrocyte gene expression. Dev. Dyn. 236, 1954-1962.
75. Kim, D.-W. and Lassar, A. B. (2003). Smad-dependent recruitment of a histone deacetylase/Sin3A complex modulates the bone morphogenetic proteindependent transcriptional repressor activity of Nkx3.2. Mol. Cell. Biol. 23, 8704-8717.
76. Kim, I. S., Otto, F., Zabel, B. and Mundlos, S. (1999). Regulation of chondrocyte differentiation by Cbfa1. Mech. Dev. 80, 159-170.
77. Kishimoto, I., Tokudome, T., Nakao, K. and Kangawa, K. (2011). Natriuretic peptide system: an overview of studies using genetically engineered animal models. FEBS J. 278, 1830-1841.
78. Kobayashi, T., Soegiarto, D. W., Yang, Y., Lanske, B., Schipani, E., McMahon, A. P. and Kronenberg, H. M. (2005). Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP. J. Clin. Invest. 115, 1734-1742.
79. Kozhemyakina, E., Cohen, T., Yao, T.-P. and Lassar, A. B. (2009). Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway. Mol. Cell. Biol. 29, 5751-5762.
80. Koziel, L., Wuelling, M., Schneider, S. and Vortkamp, A. (2005). Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation. Development 132, 5249-5260.
81. Krejci, P., Masri, B., Fontaine, V., Mekikian, P. B., Weis, M., Prats, H. and Wilcox, W. R. (2005). Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J. Cell Sci. 118, 5089-5100.
82. Krejci, P., Salazar, L., Goodridge, H. S., Kashiwada, T. A., Schibler, M. J., Jelinkova, P., Thompson, L. M. and Wilcox, W. R. (2008). STAT1 and STAT3 do not participate in FGF-mediated growth arrest in chondrocytes. J. Cell Sci. 121, 272-281.
83. Kumar, D. and Lassar, A. B. (2009). The transcriptional activity of Sox9 in chondrocytes is regulated by RhoA signaling and actin polymerization. Mol. Cell. Biol. 29, 4262-4273.
84. Kumar, D. and Lassar, A. B. (2014). Fibroblast growth factor maintains chondrogenic potential of limb bud mesenchymal cells by modulating DNMT3A recruitment. Cell Rep. 8, 1419-1431.
85. Lanske, B., Karaplis, A. C., Lee, K., Luz, A., Vortkamp, A., Pirro, A., Karperien, M., Defize, L. H. K., Ho, C., Mulligan, R. C. et al. (1996). PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663-666.
86. Lee, Y.-S. and Chuong, C.-M. (1997). Activation of protein kinase A is a pivotal step involved in both BMP-2- and cyclic AMP-induced chondrogenesis. J. Cell Physiol. 170, 153-165.
87. Lee, K., Lanske, B., Karaplis, A. C., Deeds, J. D., Kohno, H., Nissenson, R. A., Kronenberg, H. M. and Segre, G. V. (1996). Parathyroid hormone-related peptide delays terminal differentiation of chondrocytes during endochondral bone development. Endocrinology 137, 5109-5118.
88. Lefebvre, V. (2002). Toward understanding the functions of the two highly related Sox5 and Sox6 genes. J. Bone Miner. Metab. 20, 121-130.
89. Lefebvre, V., Huang, W., Harley, V. R., Goodfellow, P. N. and de Crombrugghe, B. (1997). SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol. Cell. Biol. 17, 2336-2346.
90. Lefebvre, V., Li, P. and de Crombrugghe, B. (1998). A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. EMBO J. 17, 5718-5733.
91. Leonard, C. M., Fuld, H. M., Frenz, D. A., Downie, S. A., Massague, J. and Newman, S. A. (1991). Role of transforming growth factor-beta in chondrogenic pattern formation in the embryonic limb: stimulation of mesenchymal condensation and fibronectin gene expression by exogenenous TGF-beta and evidence for endogenous TGF-beta-like activity. Dev. Biol. 145, 99-109.
92. Leung, V. Y. L., Gao, B., Leung, K. K. H., Melhado, I. G., Wynn, S. L., Au, T. Y. K., Dung, N.W. F., Lau, J. Y. B., Mak, A. C. Y., Chan, D. et al. (2011). SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet. 7, e1002356.
93. Levitt, D. and Dorfman, A. (1972). The irreversible inhibition of differentiation of limb-bud mesenchyme by bromodeoxyuridine. Proc. Natl. Acad. Sci. USA 69, 1253-1257.
94. Li, X., Deng, W., Nail, C. D., Bailey, S. K., Kraus, M. H., Ruppert, J. M. and Lobo- Ruppert, S. M. (2006). Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene 25, 609-621.
95. Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. and Efstratiadis, A. (1993). Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59-72.
96. Liu, Z., Xu, J., Colvin, J. S. and Ornitz, D. M. (2002). Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 16, 859-869.
97. Liu, Z., Lavine, K. J., Hung, I. H. and Ornitz, D. M. (2007). FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev. Biol. 302, 80-91.
98. Long, F., Zhang, X. M., Karp, S., Yang, Y. and McMahon, A. P. (2001). Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128, 5099-5108.
99. Lorget, F., Kaci, N., Peng, J., Benoist-Lasselin, C., Mugniery, E., Oppeneer, T., Wendt, D. J., Bell, S. M., Bullens, S., Bunting, S. et al. (2012). Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am. J. Hum. Genet. 91, 1108-1114.
100. Maes, C., Kobayashi, T., Selig, M. K., Torrekens, S., Roth, S. I., Mackem, S., Carmeliet, G. and Kronenberg, H. M. (2010). Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev. Cell 19, 329-344.
101. Matsushita, T., Chan, Y. Y., Kawanami, A., Balmes, G., Landreth, G. E. and Murakami, S. (2009). Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol. Cell. Biol. 29, 5843-5857.
102. McKinsey, T. A., Zhang, C. L. and Olson, E. N. (2000a). Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc. Natl. Acad. Sci. USA 97, 14400-14405.
103. McKinsey, T. A., Zhang, C.-L., Lu, J. and Olson, E. N. (2000b). Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408, 106-111.
104. Mead, T. J., Wang, Q., Bhattaram, P., Dy, P., Afelik, S., Jensen, J. and Lefebvre, V. (2013). A far-upstream(-70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration. Nucleic Acids Res. 41, 4459-4469.
105. Merino, R., Gañan, Y., Macias, D., Economides, A. N., Sampath, K. T. and Hurle, J. M. (1998). Morphogenesis of digits in the avian limb is controlled by FGFs, TGFbetas, and noggin through BMP signaling. Dev. Biol. (Orlando) 200, 35-45.
106. Minina, E., Kreschel, C., Naski, M. C., Ornitz, D. M. and Vortkamp, A. (2002). Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev. Cell 3, 439-449.
107. Minina, E., Schneider, S., Rosowski, M., Lauster, R. and Vortkamp, A. (2005). Expression of Fgf and Tgfbeta signaling related genes during embryonic endochondral ossification. Gene Expr. Patterns 6, 102-109.
108. Monsoro-Burq, A.-H. (2005). Sclerotome development and morphogenesis: when experimental embryology meets genetics. Int. J. Dev. Biol. 49, 301-308.
109. Morita, K., Miyamoto, T., Fujita, N., Kubota, Y., Ito, K., Takubo, K., Miyamoto, K., Ninomiya, K., Suzuki, T., Iwasaki, R. et al. (2007). Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification. J. Exp. Med. 204, 1613-1623.
110. Murakami, S., Kan, M., McKeehan, W. L. and de Crombrugghe, B. (2000). Upregulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 97, 1113-1118.
111. Murakami, S., Balmes, G., McKinney, S., Zhang, Z., Givol, D. and de Crombrugghe, B. (2004). Constitutive activation of MEK1 in chondrocytescauses Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3- deficient mouse phenotype. Genes Dev. 18, 290-305.
112. Murtaugh, L. C., Chyung, J. H. and Lassar, A. B. (1999). Sonic hedgehog promotes somitic chondrogenesis by altering the cellular response to BMP signaling. Genes Dev. 13, 225-237.
113. Murtaugh, L. C., Zeng, L., Chyung, J. H. and Lassar, A. B. (2001). The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMPdependent axial chondrogenesis. Dev. Cell 1, 411-422.
114. Nakao, K., Ogawa, Y., Suga, S.-i. and Imura, H. (1992). Molecular biology and biochemistry of the natriuretic peptide system. II: natriuretic peptide receptors. J. Hypertens. 10, 1111-1114.
115. Naski, M. C., Colvin, J. S., Coffin, J. D. and Ornitz, D. M. (1998). Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125, 4977-4988.
116. Ng, L.-J., Wheatley, S., Muscat, G. E. O., Conway-Campbell, J., Bowles, J., Wright, E., Bell, D. M., Tam, P. P. L., Cheah, K. S. E. and Koopman, P. (1997). SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev. Biol. 183, 108-121.
117. Niswander, L., Tickle, C., Vogel, A., Booth, I. and Martin, G. R. (1993). FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Cell 75, 579-587.
118. Nordin, K. and LaBonne, C. (2014). Sox5 is a DNA-binding cofactor for BMP Rsmads that directs target specificity during patterning of the early ectoderm. Dev. Cell 31, 374-382.
119. Nowlan, N. C., Bourdon, C., Dumas, G., Tajbakhsh, S., Prendergast, P. J. and Murphy, P. (2010). Developing bones are differentially affected by compromised skeletal muscle formation. Bone 46, 1275-1285.
120. Ornitz, D. M. and Marie, P. J. (2002). FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 16, 1446-1465.
121. Osdoby, P. and Caplan, A. I. (1979). Osteogenesis in cultures of limb mesenchymal cells. Dev. Biol. 73, 84-102.
122. Ozasa, A., Komatsu, Y., Yasoda, A., Miura, M., Sakuma, Y., Nakatsuru, Y., Arai, H., Itoh, N. and Nakao, K. (2005). Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 36, 1056-1064.
123. Peters, K., Ornitz, D., Werner, S. and Williams, L. (1993). Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev. Biol. 155, 423-430.
124. Pfander, D., Cramer, T., Schipani, E. and Johnson, R. S. (2003). HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes. J. Cell Sci. 116, 1819-1826.
125. Powell-Braxton, L., Hollingshead, P., Warburton, C., Dowd, M., Pitts-Meek, S., Dalton, D., Gillett, N. and Stewart, T. A. (1993). IGF-I is required for normal embryonic growth in mice. Genes Dev. 7, 2609-2617.
126. Provot, S., Kempf, H., Murtaugh, L. C., Chung, U.-i., Kim, D.-W., Chyung, J., Kronenberg, H. M. and Lassar, A. B. (2006). Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation. Development 133, 651-662.
127. Reginato, A. M., Iozzo, R. V. and Jimenez, S. A. (1994). Formation of nodular structures resembling mature articular cartilage in long-term primary cultures of human fetal epiphyseal chondrocytes on a hydrogel substrate. Arthritis Rheum. 37, 1338-1349.
128. Ren, P., Rowland, G. N., III and Halper, J. (1997). Expression of growth factors in chicken growth plate with special reference to tibial dyschondroplasia. J. Comp. Pathol. 116, 303-320.
129. Retting, K. N., Song, B., Yoon, B. S. and Lyons, K. M. (2009). BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 136, 1093-1104.
130. Roach, H. I., Erenpreisa, J. and Aigner, T. (1995). Osteogenic differentiation of hypertrophic chondrocytes involves asymmetric cell divisions and apoptosis. J. Cell Biol. 131, 483-494.
131. Roark, E. F. and Greer, K. (1994). Transforming growth factor-beta and bone morphogenetic protein-2 act by distinct mechanisms to promote chick limb cartilage differentiation in vitro. Dev. Dyn. 200, 103-116.
132. Roddy, K. A., Prendergast, P. J. and Murphy, P. (2011). Mechanical influences on morphogenesis of the knee joint revealed through morphological, molecular and computational analysis of immobilised embryos. PLoS ONE 6, e17526.
133. Rot, C., Stern, T., Blecher, R., Friesem, B. and Zelzer, E. (2014). A mechanical jack-like mechanism drives spontaneous fracture healing in neonatal mice. Dev. Cell 31, 159-170.
134. Rot-Nikcevic, I., Reddy, T., Downing, K. J., Belliveau, A. C., Hallgrıìmsson, B., Hall, B. K. and Kablar, B. (2006). Myf5-/-:MyoD-/- amyogenic fetuses reveal the importance of early contraction and static loading by striated muscle in mouse skeletogenesis. Dev. Genes Evol. 216, 1-9.
135. Rudnicki, J. A. and Brown, A. M. C. (1997). Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro. Dev. Biol. 185, 104-118.
136. Sahni, M., Ambrosetti, D.-C., Mansukhani, A., Gertner, R., Levy, D. and Basilico, C. (1999). FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev. 13, 1361-1366.
137. Sahni, M., Raz, R., Coffin, J. D., Levy, D. and Basilico, C. (2001). STAT1 mediates the increased apoptosis and reduced chondrocyte proliferation in mice overexpressing FGF2. Development 128, 2119-2129.
138. Sasagawa, S., Takemori, H., Uebi, T., Ikegami, D., Hiramatsu, K., Ikegawa, S., Yoshikawa, H. and Tsumaki, N. (2012). SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice. Development 139, 1153-1163.
139. Schipani, E., Ryan, H. E., Didrickson, S., Kobayashi, T., Knight, M. and Johnson, R. S. (2001). Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev. 15, 2865-2876.
140. Segev, O., Chumakov, I., Nevo, Z., Givol, D., Madar-Shapiro, L., Sheinin, Y., Weinreb, M. and Yayon, A. (2000). Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice. Hum. Mol. Genet. 9, 249-258.
141. Selvamurugan, N., Pulumati, M. R., Tyson, D. R. and Partridge, N. C. (2000). Parathyroid hormone regulation of the rat collagenase-3 promoter by protein kinase A-dependent transactivation of core binding factor alpha1. J. Biol. Chem. 275, 5037-5042.
142. Seo, H.-S. and Serra, R. (2007). Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev. Biol. 310, 304-316.
143. Shapiro, I. M., Adams, C. S., Freeman, T. and Srinivas, V. (2005). Fate of the hypertrophic chondrocyte: microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate. Birth Defects Res. C Embryo Today 75, 330-339.
144. Shen, W., Scearce, L. M., Brestelli, J. E., Sund, N. J. and Kaestner, K. H. (2001). Foxa3 (hepatocyte nuclear factor 3gamma) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast. J. Biol. Chem. 276, 42812-42817.
145. Shwartz, Y., Farkas, Z., Stern, T., Aszoòdi, A. and Zelzer, E. (2012). Muscle contraction controls skeletal morphogenesis through regulation of chondrocyte convergent extension. Dev. Biol. 370, 154-163.
146. Smits, P., Li, P., Mandel, J., Zhang, Z., Deng, J. M., Behringer, R. R., de Crombrugghe, B. and Lefebvre, V. (2001). The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev. Cell 1, 277-290.
147. Solursh, M. (1984). Ectoderm as a determinant of early tissue pattern in the limb bud. Cell Differ. 15, 17-24.
148. Solursh, M. and Reiter, R. S. (1975). Determination of limb bud chondrocytes during a transient block of the cell cycle. Cell Differ. 4, 131-137.
149. Solursh, M., Linsenmayer, T. F. and Jensen, K. L. (1982). Chondrogenesis from single limb mesenchyme cells. Dev. Biol. 94, 259-264.
150. Spagnoli, A., O’Rear, L., Chandler, R. L., Granero-Molto, F., Mortlock, D. P., Gorska, A. E., Weis, J. A., Longobardi, L., Chytil, A., Shimer, K. et al. (2007). TGF-beta signaling is essential for joint morphogenesis. J. Cell Biol. 177, 1105-1117.
151. Spaäter, D., Hill, T. P., O’Sullivan, R. J., Gruber, M., Conner, D.A. and Hartmann, C. (2006). Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development 133, 3039-3049.
152. St-Jacques, B., Hammerschmidt, M. and McMahon, A. P. (1999). Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072-2086.
153. Stafford, D. A., Brunet, L. J., Khokha, M. K., Economides, A. N. and Harland, R. M. (2011). Cooperative activity of noggin and gremlin 1 in axial skeleton development. Development 138, 1005-1014.
154. Stickens, D., Behonick, D. J., Ortega, N., Heyer, B., Hartenstein, B., Yu, Y., Fosang, A. J., Schorpp-Kistner, M., Angel, P. and Werb, Z. (2004). Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131, 5883-5895.
155. Stricker, S., Fundele, R., Vortkamp, A. and Mundlos, S. (2002). Role of Runx genes in chondrocyte differentiation. Dev. Biol. 245, 95-108.
156. Sugimoto, Y., Takimoto, A., Akiyama, H., Kist, R., Scherer, G., Nakamura, T., Hiraki, Y. and Shukunami, C. (2013). Scx+/Sox9+ progenitors contribute to the establishment of the junction between cartilage and tendon/ligament. Development 140, 2280-2288.
157. Sun, X., Mariani, F. V. and Martin, G. R. (2002). Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418, 501-508.
158. Takeda, S., Bonnamy, J.-P., Owen, M. J., Ducy, P. and Karsenty, G. (2001). Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev. 15, 467-481.
159. Tamamura, Y., Otani, T., Kanatani, N., Koyama, E., Kitagaki, J., Komori, T., Yamada, Y., Costantini, F., Wakisaka, S., Pacifici, M. et al. (2005). Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J. Biol. Chem. 280, 19185-19195.
160. Tamura, N., Doolittle, L. K., Hammer, R. E., Shelton, J. M., Richardson, J. A. and Garbers, D. L. (2004). Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. Proc. Natl. Acad. Sci. USA 101, 17300-17305.
161. Teillet, M., Watanabe, Y., Jeffs, P., Duprez, D., Lapointe, F. and Le Douarin, N. M. (1998). Sonic hedgehog is required for survival of both myogenic and chondrogenic somitic lineages. Development 125, 2019-2030.
162. Ten Berge, D., Brugmann, S. A., Helms, J. A. and Nusse, R. (2008). Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development. Development 135, 3247-3257.
163. Topol, L., Chen, W., Song, H., Day, T. F. and Yang, Y. (2009). Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus. J. Biol. Chem. 284, 3323-3333.
164. Tsuji, T. and Kunieda, T. (2005). A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J. Biol. Chem. 280, 14288-14292.
165. Ueta, C., Iwamoto, M., Kanatani, N., Yoshida, C., Liu, Y., Enomoto-Iwamoto, M., Ohmori, T., Enomoto, H., Nakata, K., Takada, K. et al. (2001). Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J. Cell Biol. 153, 87-100.
166. Usmani, S. E., Pest, M. A., Kim, G., Ohora, S. N., Qin, L. and Beier, F. (2012). Transforming growth factor alpha controls the transition from hypertrophic cartilage to bone during endochondral bone growth. Bone 51, 131-141.
167. Vega, R. B., Matsuda, K., Oh, J., Barbosa, A. C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A. et al. (2004). Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119, 555-566.
168. Vortkamp, A., Lee, K., Lanske, B., Segre, G. V., Kronenberg, H. M. and Tabin, C. J. (1996). Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613-622.
169. Wang, X. and Mao, J. J. (2002). Chondrocyte proliferation of the cranial base cartilage upon in vivo mechanical stresses. J. Dent. Res. 81, 701-705.
170. Wang, A. H. and Yang, X.-J. (2001). Histone deacetylase 4 possesses intrinsic nuclear import and export signals. Mol. Cell. Biol. 21, 5992-6005.
171. Wang, J., Zhou, J. and Bondy, C. A. (1999a). Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J. 13, 1985-1990.
172. Wang, Y., Spatz, M. K., Kannan, K., Hayk, H., Avivi, A., Gorivodsky, M., Pines, M., Yayon, A., Lonai, P. and Givol, D. (1999b). A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc. Natl. Acad. Sci. USA 96, 4455-4460.
173. Wang, A. H., Kruhlak, M. J., Wu, J., Bertos, N. R., Vezmar, M., Posner, B. I., Bazett-Jones, D. P. and Yang, X.-J. (2000). Regulation of histone deacetylase 4 by binding of 14–3-3 proteins. Mol. Cell. Biol. 20, 6904-6912.
174. Weir, E. C., Philbrick, W. M., Amling, M., Neff, L. A., Baron, R. and Broadus, A. E. (1996). Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc. Natl. Acad. Sci. USA 93, 10240-10245.
175. Weston, A. D., Chandraratna, R. A. S., Torchia, J. and Underhill, T. M. (2002). Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. J. Cell Biol. 158, 39-51.
176. Wilson, C. W. and Chuang, P.-T. (2010). Mechanism and evolution of cytosolic Hedgehog signal transduction. Development 137, 2079-2094.
177. Woods, A. and Beier, F. (2006). RhoA/ROCK signaling regulates chondrogenesis in a context-dependent manner. J. Biol. Chem. 281, 13134-13140.
178. Woods, K. A., Camacho-Huübner, C., Savage, M. O. and Clark, A. J. L. (1996). Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N. Engl. J. Med. 335, 1363-1367.
179. Woods, A., Wang, G. and Beier, F. (2005). RhoA/ROCK signaling regulates Sox9 expression and actin organization during chondrogenesis. J. Biol. Chem. 280, 11626-11634.
180. Yamashita, Y., Takeshige, K., Inoue, A., Hirose, S., Takamori, A. and Hagiwara, H. (2000). Concentration of mRNA for the natriuretic peptide receptor-C in hypertrophic chondrocytes of the fetal mouse tibia. J. Biochem. 127, 177-179.
181. Yang, L., Tsang, K. Y., Tang, H. C., Chan, D. and Cheah, K. S. E. (2014). Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc. Natl. Acad. Sci. USA 111, 12097-12102.
182. Yasoda, A., Komatsu, Y., Chusho, H., Miyazawa, T., Ozasa, A., Miura, M., Kurihara, T., Rogi, T., Tanaka, S., Suda, M. et al. (2004). Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat. Med. 10, 80-86.
183. Yasoda, A., Kitamura, H., Fujii, T., Kondo, E., Murao, N., Miura, M., Kanamoto, N., Komatsu, Y., Arai, H. and Nakao, K. (2009). Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology 150, 3138-3144.
184. Yasuhara, R., Yuasa, T., Williams, J. A., Byers, S. W., Shah, S., Pacifici, M., Iwamoto, M. and Enomoto-Iwamoto, M. (2010). Wnt/beta-catenin and retinoic acid receptor signaling pathways interact to regulate chondrocyte function and matrix turnover. J. Biol. Chem. 285, 317-327.
185. Yoon, Y.-M., Oh, C.-D., Kang, S.-S. and Chun, J.-S. (2000). Protein kinase A regulates chondrogenesis of mesenchymal cells at the post-precartilage condensation stage via protein kinase C-alpha signaling. J. Bone Miner. Res. 15, 2197-2205.
186. Yoon, B. S., Ovchinnikov, D. A., Yoshii, I., Mishina, Y., Behringer, R. R. and Lyons, K. M. (2005). Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc. Natl. Acad. Sci. USA 102, 5062-5067.
187. Yoon, B. S., Pogue, R., Ovchinnikov, D. A., Yoshii, I., Mishina, Y., Behringer, R. R. and Lyons, K. M. (2006). BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways. Development 133, 4667-4678.
188. Yoshida, C. A., Yamamoto, H., Fujita, T., Furuichi, T., Ito, K., Inoue, K.-i., Yamana, K., Zanma, A., Takada, K., Ito, Y. et al. (2004). Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev. 18, 952-963.
189. Yu, K., Xu, J., Liu, Z., Sosic, D., Shao, J., Olson, E. N., Towler, D. A. and Ornitz, D. M. (2003). Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development 130, 3063-3074.
190. Zanetti, N. C. and Solursh, M. (1984). Induction of chondrogenesis in limb mesenchymal cultures by disruption of the actin cytoskeleton. J. Cell Biol. 99, 115-123.
191. Zelzer, E., Glotzer, D. J., Hartmann, C., Thomas, D., Fukai, N., Soker, S. and Olsen, B. R. (2001). Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mech. Dev. 106, 97-106.
192. Zelzer, E., McLean, W., Ng, Y. S., Fukai, N., Reginato, A. M., Lovejoy, S., D’Amore, P. A. and Olsen, B. R. (2002). Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129, 1893-1904.
193. Zelzer, E., Mamluk, R., Ferrara, N., Johnson, R. S., Schipani, E. and Olsen, B. R. (2004). VEGFA is necessary for chondrocyte survival during bone development. Development 131, 2161-2171.
194. Zeng, L., Kempf, H., Murtaugh, L. C., Sato, M. E. and Lassar, A. B. (2002). Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis. Genes Dev. 16, 1990-2005.
195. Zhang, Y.-W., Yasui, N., Ito, K., Huang, G., Fujii, M., Hanai, J.-i., Nogami, H., Ochi, T., Miyazono, K. and Ito, Y. (2000). A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc. Natl. Acad. Sci. USA 97, 10549-10554.
196. Zhang, X., Siclari, V. A., Lan, S., Zhu, J., Koyama, E., Dupuis, H. L., Enomoto- Iwamoto, M., Beier, F. and Qin, L. (2011). The critical role of the epidermal growth factor receptor in endochondral ossification. J. Bone Miner. Res. 26, 2622-2633.
197. Zhang, X., Zhu, J., Li, Y., Lin, T., Siclari, V. A., Chandra, A., Candela, E. M., Koyama, E., Enomoto-Iwamoto, M. and Qin, L. (2013). Epidermal growth factor receptor (EGFR) signaling regulates epiphyseal cartilage development through beta-catenin-dependent and -independent pathways. J. Biol. Chem. 288, 32229-32240.
198. Zheng, Q., Zhou, G., Morello, R., Chen, Y., Garcia-Rojas, X. and Lee, B. (2003). Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J. Cell Biol. 162, 833-842.
199. Zhou, G., Lefebvre, V., Zhang, Z., Eberspaecher, H. and de Crombrugghe, B. (1998). Three high mobility group-like sequences within a 48-base pair enhancer of the Col2a1 gene are required for cartilage-specific expression in vivo. J. Biol. Chem. 273, 14989-14997.
200. Zhou, G., Zheng, Q., Engin, F., Munivez, E., Chen, Y., Sebald, E., Krakow, D. and Lee, B. (2006). Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc. Natl. Acad. Sci. USA 103, 19004-19009.
201. Zou, H., Wieser, R., Massague, J. and Niswander, L. (1997). Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev. 11, 2191-2203.