Cellular and Molecular Life Sciences

, Volume 70, Issue 22, pp 4213–4221 | Cite as

Regulatory mechanisms for the development of growth plate cartilage

  • Toshimi Michigami


In vertebrates, most of the skeleton is formed through endochondral ossification. Endochondral bone formation is a complex process involving the mesenchymal condensation of undifferentiated cells, the proliferation of chondrocytes and their differentiation into hypertrophic chondrocytes, and mineralization. This process is tightly regulated by various factors including transcription factors, soluble mediators, extracellular matrices, and cell–cell and cell–matrix interactions. Defects of these factors often lead to skeletal dysplasias and short stature. Moreover, there is growing evidence that epigenetic and microRNA-mediated mechanisms also play critical roles in chondrogenesis. This review provides an overview of our current understanding of the regulators for the development of growth plate cartilage and their molecular mechanisms of action. A knowledge of the regulatory mechanisms underlying the proliferation and differentiation of chondrocytes will provide insights into future therapeutic options for skeletal disorders.


Chondrocyte Transcription factors Growth factors Extracellular matrix Differentiation 


  1. 1.
    Wagner EF, Karsenty G (2001) Genetic control of skeletal development. Curr Opin Genet Dev 11:527–532PubMedGoogle Scholar
  2. 2.
    Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336PubMedGoogle Scholar
  3. 3.
    Lefebvre V, Bhattaram P (2010) Vertebrate skeletogenesis. Curr Top Dev Biol 90:291–317PubMedGoogle Scholar
  4. 4.
    Beier F (2005) Cell-cycle control and the cartilage growth plate. J Cell Physiol 202:1–8PubMedGoogle Scholar
  5. 5.
    Burdan F, Szumilo J, Korobowicz A, Farooquee R, Patel S, Patel A, Dave A, Szumilo M, Solecki M, Klepacz R, Dudka J (2009) Morphology and physiology of the epiphyseal growth plate. Folia Histochem Cytobiol 47:5–16PubMedGoogle Scholar
  6. 6.
    Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR (2004) VEGFA is necessary for chondrocyte survival during bone development. Development 131:2161–2171PubMedGoogle Scholar
  7. 7.
    Stickens D, Behonick DJ, Ortega N, Heyer B, Hartenstein B, Yu Y, Fosang AJ, Schorpp-Kistner M, Angel P, Werb Z (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895PubMedGoogle Scholar
  8. 8.
    Hartmann C (2009) Transcriptional networks controlling skeletal development. Curr Opin Genet Dev 19:437–443PubMedGoogle Scholar
  9. 9.
    Nishimura R, Hata K, Matsubara T, Wakabayashi M, Yoneda T (2012) Regulation of bone and cartilage development by network between BMP signalling and transcription factors. J Biochem 151:247–254PubMedGoogle Scholar
  10. 10.
    Woods A, Wang G, Beier F (2007) Regulation of chondrocyte differentiation by the actin cytoskeleton and adhesive interactions. J Cell Physiol 213:1–8PubMedGoogle Scholar
  11. 11.
    Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A (2011) Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 155A:943–968PubMedGoogle Scholar
  12. 12.
    Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN et al (1994) Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372:525–530PubMedGoogle Scholar
  13. 13.
    Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E, Wolf U, Tommerup N, Schempp W, Scherer G (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111–1120PubMedGoogle Scholar
  14. 14.
    Akiyama H, Lefebvre V (2011) Unraveling the transcriptional regulatory machinery in chondrogenesis. J Bone Miner Metab 29:390–395PubMedGoogle Scholar
  15. 15.
    Lefebvre V, Li P, 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 17:5718–5733PubMedGoogle Scholar
  16. 16.
    Lefebvre V, Huang W, Harley VR, Goodfellow PN, de Crombrugghe B (1997) SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 17:2336–2346PubMedGoogle Scholar
  17. 17.
    Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16:2813–2828PubMedGoogle Scholar
  18. 18.
    Han Y, Lefebvre V (2008) L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer. Mol Cell Biol 28:4999–5013PubMedGoogle Scholar
  19. 19.
    Long F, Zhang XM, Karp S, Yang Y, McMahon AP (2001) Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128:5099–5108PubMedGoogle Scholar
  20. 20.
    Vale-Cruz DS, Ma Q, Syme J, LuValle PA (2008) Activating transcription factor-2 affects skeletal growth by modulating pRb gene expression. Mech Dev 125:843–856PubMedGoogle Scholar
  21. 21.
    Wang ZQ, Ovitt C, Grigoriadis AE, Mohle-Steinlein U, Ruther U, Wagner EF (1992) Bone and haematopoietic defects in mice lacking c-fos. Nature 360:741–745PubMedGoogle Scholar
  22. 22.
    Woods A, Wang G, Beier F (2005) RhoA/ROCK signaling regulates Sox9 expression and actin organization during chondrogenesis. J Biol Chem 280:11626–11634PubMedGoogle Scholar
  23. 23.
    Woods A, Beier F (2006) RhoA/ROCK signaling regulates chondrogenesis in a context-dependent manner. J Biol Chem 281:13134–13140PubMedGoogle Scholar
  24. 24.
    Yoshida CA, Komori T (2005) Role of Runx proteins in chondrogenesis. Crit Rev Eukaryot Gene Expr 15:243–254PubMedGoogle Scholar
  25. 25.
    Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B (2003) Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol 162:833–842PubMedGoogle Scholar
  26. 26.
    Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y, Komori T (2004) Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev 18:952–963PubMedGoogle Scholar
  27. 27.
    Selvamurugan N, Kwok S, Partridge NC (2004) Smad3 interacts with JunB and Cbfa1/Runx2 for transforming growth factor-beta1-stimulated collagenase-3 expression in human breast cancer cells. J Biol Chem 279:27764–27773PubMedGoogle Scholar
  28. 28.
    Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock RT, Lefebvre V (2012) Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell 22:597–609PubMedGoogle Scholar
  29. 29.
    Hinoi E, Bialek P, Chen YT, Rached MT, Groner Y, Behringer RR, Ornitz DM, Karsenty G (2006) Runx2 inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondrium. Genes Dev 20:2937–2942PubMedGoogle Scholar
  30. 30.
    Nishimura R, Wakabayashi M, Hata K, Matsubara T, Honma S, Wakisaka S, Kiyonari H, Shioi G, Yamaguchi A, Tsumaki N, Akiyama H, Yoneda T (2012) Osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13 (MMP13) expression in association with transcription factor Runx2 during endochondral ossification. J Biol Chem 287:33179–33190PubMedGoogle Scholar
  31. 31.
    Arnold MA, Kim Y, Czubryt MP, Phan D, McAnally J, Qi X, Shelton JM, Richardson JA, Bassel-Duby R, Olson EN (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell 12:377–389PubMedGoogle Scholar
  32. 32.
    Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, McAnally J, Pomajzl C, Shelton JM, Richardson JA, Karsenty G, Olson EN (2004) Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119:555–566PubMedGoogle Scholar
  33. 33.
    Kozhemyakina E, Cohen T, Yao TP, Lassar AB (2009) Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway. Mol Cell Biol 29:5751–5762PubMedGoogle Scholar
  34. 34.
    Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, Maeda T, Takano Y, Uchiyama M, Heaney S, Peters H, Tang Z, Maxson R, Maas R (2000) Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 24:391–395PubMedGoogle Scholar
  35. 35.
    Amano K, Ichida F, Sugita A, Hata K, Wada M, Takigawa Y, Nakanishi M, Kogo M, Nishimura R, Yoneda T (2008) MSX2 stimulates chondrocyte maturation by controlling Ihh expression. J Biol Chem 283:29513–29521PubMedGoogle Scholar
  36. 36.
    Karreth F, Hoebertz A, Scheuch H, Eferl R, Wagner EF (2004) The AP1 transcription factor Fra2 is required for efficient cartilage development. Development 131:5717–5725PubMedGoogle Scholar
  37. 37.
    Ionescu A, Kozhemyakina E, Nicolae C, Kaestner KH, Olsen BR, Lassar AB (2012) FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program. Dev Cell 22:927–939PubMedGoogle Scholar
  38. 38.
    Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS (2001) Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev 15:2865–2876PubMedGoogle Scholar
  39. 39.
    Maes C, Araldi E, Haigh K, Khatri R, Van Looveren R, Giaccia AJ, Haigh JJ, Carmeliet G, Schipani E (2012) VEGF-independent cell-autonomous functions of HIF-1alpha regulating oxygen consumption in fetal cartilage are critical for chondrocyte survival. J Bone Miner Res 27:596–609PubMedGoogle Scholar
  40. 40.
    Bentovim L, Amarilio R, Zelzer E (2012) HIF1alpha is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development. Development 139:4473–4483PubMedGoogle Scholar
  41. 41.
    Kronenberg HM (2006) PTHrP and skeletal development. Ann N Y Acad Sci 1068:1–13PubMedGoogle Scholar
  42. 42.
    St-Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13:2072–2086PubMedGoogle Scholar
  43. 43.
    Kobayashi T, Soegiarto DW, Yang Y, Lanske B, Schipani E, McMahon AP, Kronenberg HM (2005) Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP. J Clin Invest 115:1734–1742PubMedGoogle Scholar
  44. 44.
    Mak KK, Kronenberg HM, Chuang PT, Mackem S, Yang Y (2008) Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135:1947–1956PubMedGoogle Scholar
  45. 45.
    Ornitz DM (2005) FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 16:205–213PubMedGoogle Scholar
  46. 46.
    Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254PubMedGoogle Scholar
  47. 47.
    Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335–342PubMedGoogle Scholar
  48. 48.
    Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10:357–359PubMedGoogle Scholar
  49. 49.
    Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321–328PubMedGoogle Scholar
  50. 50.
    Sullivan R, Klagsbrun M (1985) Purification of cartilage-derived growth factor by heparin affinity chromatography. J Biol Chem 260:2399–2403PubMedGoogle Scholar
  51. 51.
    Hurley MM, Abreu C, Gronowicz G, Kawaguchi H, Lorenzo J (1994) Expression and regulation of basic fibroblast growth factor mRNA levels in mouse osteoblastic MC3T3-E1 cells. J Biol Chem 269:9392–9396PubMedGoogle Scholar
  52. 52.
    Montero A, Okada Y, Tomita M, Ito M, Tsurukami H, Nakamura T, Doetschman T, Coffin JD, Hurley MM (2000) Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J Clin Invest 105:1085–1093PubMedGoogle Scholar
  53. 53.
    Colvin JS, Feldman B, Nadeau JH, Goldfarb M, Ornitz DM (1999) Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Dev Dyn 216:72–88PubMedGoogle Scholar
  54. 54.
    Finch PW, Cunha GR, Rubin JS, Wong J, Ron D (1995) Pattern of keratinocyte growth factor and keratinocyte growth factor receptor expression during mouse fetal development suggests a role in mediating morphogenetic mesenchymal-epithelial interactions. Dev Dyn 203:223–240PubMedGoogle Scholar
  55. 55.
    Mason IJ, Fuller-Pace F, Smith R, Dickson C (1994) FGF-7 (keratinocyte growth factor) expression during mouse development suggests roles in myogenesis, forebrain regionalisation and epithelial-mesenchymal interactions. Mech Dev 45:15–30PubMedGoogle Scholar
  56. 56.
    Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N, Takada S (2002) FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev 16:870–879PubMedGoogle Scholar
  57. 57.
    Liu Z, Xu J, Colvin JS, Ornitz DM (2002) Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 16:859–869PubMedGoogle Scholar
  58. 58.
    Xu J, Lawshe A, MacArthur CA, Ornitz DM (1999) Genomic structure, mapping, activity and expression of fibroblast growth factor 17. Mech Dev 83(1–2):165–178PubMedGoogle Scholar
  59. 59.
    Hung IH, Yu K, Lavine KJ, Ornitz DM (2007) FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol 307:300–313PubMedGoogle Scholar
  60. 60.
    Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84:911–921PubMedGoogle Scholar
  61. 61.
    Peters KG, Werner S, Chen G, Williams LT (1992) Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development 114:233–243PubMedGoogle Scholar
  62. 62.
    Peters K, Ornitz D, Werner S, Williams L (1993) Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol 155:423–430PubMedGoogle Scholar
  63. 63.
    Chen L, Adar R, Yang X, Monsonego EO, Li C, Hauschka PV, Yayon A, Deng CX (1999) Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J Clin Invest 104:1517–1525PubMedGoogle Scholar
  64. 64.
    Chen L, Li C, Qiao W, Xu X, Deng C (2001) A Ser(365)→Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 10:457–465PubMedGoogle Scholar
  65. 65.
    Dailey L, Laplantine E, Priore R, Basilico C (2003) A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation. J Cell Biol 161:1053–1066PubMedGoogle Scholar
  66. 66.
    Li C, Chen L, Iwata T, Kitagawa M, Fu XY, Deng CX (1999) A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. Hum Mol Genet 8:35–44PubMedGoogle Scholar
  67. 67.
    Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A (2002) Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell 3:439–449PubMedGoogle Scholar
  68. 68.
    Anand-Srivastava MB (2005) Natriuretic peptide receptor-C signaling and regulation. Peptides 26:1044–1059PubMedGoogle Scholar
  69. 69.
    Baxter GF (2004) The natriuretic peptides. Basic Res Cardiol 99:71–75PubMedGoogle Scholar
  70. 70.
    Teixeira CC, Agoston H, Beier F (2008) Nitric oxide, C-type natriuretic peptide and cGMP as regulators of endochondral ossification. Dev Biol 319:171–178PubMedGoogle Scholar
  71. 71.
    Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T, Nakamura K, Nakao K, Kurihara T, Komatsu Y, Itoh H, Tanaka K, Saito Y, Katsuki M (2001) Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc Natl Acad Sci USA 98:4016–4021PubMedGoogle Scholar
  72. 72.
    Yasoda A, Ogawa Y, Suda M, Tamura N, Mori K, Sakuma Y, Chusho H, Shiota K, Tanaka K, Nakao K (1998) Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. J Biol Chem 273:11695–11700PubMedGoogle Scholar
  73. 73.
    Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M, Tamura N, Ogawa Y, Nakao K (2004) Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80–86PubMedGoogle Scholar
  74. 74.
    Bartels CF, Bukulmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih LY, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, Kirk J, Mortier GR, Leroy J, Zabel B, Kim CA, Crow Y, Braverman NE, van den Akker F, Warman ML (2004) Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 75:27–34PubMedGoogle Scholar
  75. 75.
    Miura K, Namba N, Fujiwara M, Ohata Y, Ishida H, Kitaoka T, Kubota T, Hirai H, Higuchi C, Tsumaki N, Yoshikawa H, Sakai N, Michigami T, Ozono K (2012) An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. PLoS ONE 7:e42180PubMedGoogle Scholar
  76. 76.
    Ulici V, Hoenselaar KD, Gillespie JR, Beier F (2008) The PI3K pathway regulates endochondral bone growth through control of hypertrophic chondrocyte differentiation. BMC Dev Biol 8:40PubMedGoogle Scholar
  77. 77.
    Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, Wendt DJ, Bell SM, Bullens S, Bunting S, Tsuruda LS, O’Neill CA, Di Rocco F, Munnich A, Legeai-Mallet L (2012) Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 91:1108–1114PubMedGoogle Scholar
  78. 78.
    Wang K, Yamamoto H, Chin JR, Werb Z, Vu TH (2004) Epidermal growth factor receptor-deficient mice have delayed primary endochondral ossification because of defective osteoclast recruitment. J Biol Chem 279:53848–53856PubMedGoogle Scholar
  79. 79.
    Schneider MR, Mayer-Roenne B, Dahlhoff M, Proell V, Weber K, Wolf E, Erben RG (2009) High cortical bone mass phenotype in betacellulin transgenic mice is EGFR dependent. J Bone Miner Res 24:455–467PubMedGoogle Scholar
  80. 80.
    Zhang X, Siclari VA, Lan S, Zhu J, Koyama E, Dupuis HL, Enomoto-Iwamoto M, Beier F, Qin L (2011) The critical role of the epidermal growth factor receptor in endochondral ossification. J Bone Miner Res 26:2622–2633PubMedGoogle Scholar
  81. 81.
    Pogue R, Lyons K (2006) BMP signaling in the cartilage growth plate. Curr Top Dev Biol 76:1–48PubMedGoogle Scholar
  82. 82.
    Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M (2008) Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol 40:46–62PubMedGoogle Scholar
  83. 83.
    Olney RC, Mougey EB (1999) Expression of the components of the insulin-like growth factor axis across the growth-plate. Mol Cell Endocrinol 156:63–71PubMedGoogle Scholar
  84. 84.
    Oberlender SA, Tuan RS (1994) Expression and functional involvement of N-cadherin in embryonic limb chondrogenesis. Development 120:177–187PubMedGoogle Scholar
  85. 85.
    Tavella S, Raffo P, Tacchetti C, Cancedda R, Castagnola P (1994) N-CAM and N-cadherin expression during in vitro chondrogenesis. Exp Cell Res 215:354–362PubMedGoogle Scholar
  86. 86.
    ffrench-Constant C, Colognato H (2004) Integrins: versatile integrators of extracellular signals. Trends Cell Biol 14:678–686PubMedGoogle Scholar
  87. 87.
    Clancy RM, Rediske J, Tang X, Nijher N, Frenkel S, Philips M, Abramson SB (1997) Outside-in signaling in the chondrocyte. Nitric oxide disrupts fibronectin-induced assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling complex. J Clin Invest 100:1789–1796PubMedGoogle Scholar
  88. 88.
    Legate KR, Wickstrom SA, Fassler R (2009) Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev 23:397–418PubMedGoogle Scholar
  89. 89.
    Shakibaei M (1995) Integrin expression on epiphyseal mouse chondrocytes in monolayer culture. Histol Histopathol 10:339–349PubMedGoogle Scholar
  90. 90.
    Loeser RF (2000) Chondrocyte integrin expression and function. Biorheology 37:109–116PubMedGoogle Scholar
  91. 91.
    Loeser RF (2002) Integrins and cell signaling in chondrocytes. Biorheology 39:119–124PubMedGoogle Scholar
  92. 92.
    Egerbacher M, Haeusler G (2003) Integrins in growth plate cartilage. Pediatr Endocrinol Rev 1:2–8PubMedGoogle Scholar
  93. 93.
    Aszodi A, Hunziker EB, Brakebusch C, Fassler R (2003) Beta1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis. Genes Dev 17:2465–2479PubMedGoogle Scholar
  94. 94.
    Bengtsson T, Aszodi A, Nicolae C, Hunziker EB, Lundgren-Akerlund E, Fassler R (2005) Loss of alpha10beta1 integrin expression leads to moderate dysfunction of growth plate chondrocytes. J Cell Sci 118:929–936PubMedGoogle Scholar
  95. 95.
    Zemmyo M, Meharra EJ, Kuhn K, Creighton-Achermann L, Lotz M (2003) Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice. Arthritis Rheum 48:2873–2880PubMedGoogle Scholar
  96. 96.
    Terpstra L, Prud’homme J, Arabian A, Takeda S, Karsenty G, Dedhar S, St-Arnaud R (2003) Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes. J Cell Biol 162:139–148PubMedGoogle Scholar
  97. 97.
    Nicoll SB, Barak O, Csoka AB, Bhatnagar RS, Stern R (2002) Hyaluronidases and CD44 undergo differential modulation during chondrogenesis. Biochem Biophys Res Commun 292:819–825PubMedGoogle Scholar
  98. 98.
    Lucic D, Mollenhauer J, Kilpatrick KE, Cole AA (2003) N-telopeptide of type II collagen interacts with annexin V on human chondrocytes. Connect Tissue Res 44:225–239PubMedGoogle Scholar
  99. 99.
    Reid DL, Aydelotte MB, Mollenhauer J (2000) Cell attachment, collagen binding, and receptor analysis on bovine articular chondrocytes. J Orthop Res 18:364–373PubMedGoogle Scholar
  100. 100.
    Kirsch T (2005) Annexins—their role in cartilage mineralization. Front Biosci 10:576–581PubMedGoogle Scholar
  101. 101.
    Mertz EL, Facchini M, Pham AT, Gualeni B, De Leonardis F, Rossi A, Forlino A (2012) Matrix disruptions, growth, and degradation of cartilage with impaired sulfation. J Biol Chem 287:22030–22042PubMedGoogle Scholar
  102. 102.
    Sato T, Kudo T, Ikehara Y, Ogawa H, Hirano T, Kiyohara K, Hagiwara K, Togayachi A, Ema M, Takahashi S, Kimata K, Watanabe H, Narimatsu H (2011) Chondroitin sulfate N-acetylgalactosaminyltransferase 1 is necessary for normal endochondral ossification and aggrecan metabolism. J Biol Chem 286:5803–5812PubMedGoogle Scholar
  103. 103.
    Pedrozo HA, Schwartz Z, Gomez R, Ornoy A, Xin-Sheng W, Dallas SL, Bonewald LF, Dean DD, Boyan BD (1998) Growth plate chondrocytes store latent transforming growth factor (TGF)-beta 1 in their matrix through latent TGF-beta 1 binding protein-1. J Cell Physiol 177:343–354PubMedGoogle Scholar
  104. 104.
    Pedrozo HA, Schwartz Z, Mokeyev T, Ornoy A, Xin-Sheng W, Bonewald LF, Dean DD, Boyan BD (1999) Vitamin D3 metabolites regulate LTBP1 and latent TGF-beta1 expression and latent TGF-beta1 incorporation in the extracellular matrix of chondrocytes. J Cell Biochem 72:151–165PubMedGoogle Scholar
  105. 105.
    Hildebrand A, Romaris M, Rasmussen LM, Heinegard D, Twardzik DR, Border WA, Ruoslahti E (1994) Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J 302:527–534PubMedGoogle Scholar
  106. 106.
    Settembre C, Arteaga-Solis E, McKee MD, de Pablo R, Al Awqati Q, Ballabio A, Karsenty G (2008) Proteoglycan desulfation determines the efficiency of chondrocyte autophagy and the extent of FGF signaling during endochondral ossification. Genes Dev 22:2645–2650PubMedGoogle Scholar
  107. 107.
    Koshimizu T, Kawai M, Kondou H, Tachikawa K, Sakai N, Ozono K, Michigami T (2010) Vinculin functions as regulator of chondrogenesis. J Biol Chem 287:15760–15775Google Scholar
  108. 108.
    Goldring MB, Marcu KB (2012) Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis. Trends Mol Med 18:109–118PubMedGoogle Scholar
  109. 109.
    Hong S, Derfoul A, Pereira-Mouries L, Hall DJ (2009) A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes. FASEB J 23:3539–3552PubMedGoogle Scholar
  110. 110.
    Higashiyama R, Miyaki S, Yamashita S, Yoshitaka T, Lindman G, Ito Y, Sasho T, Takahashi K, Lotz M, Asahara H (2010) Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. Mod Rheumatol 20:11–17PubMedGoogle Scholar
  111. 111.
    Dvir-Ginzberg M, Gagarina V, Lee EJ, Hall DJ (2008) Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase. J Biol Chem 283:36300–36310PubMedGoogle Scholar
  112. 112.
    Gabay O, Oppenhiemer H, Meir H, Zaal K, Sanchez C, Dvir-Ginzberg M (2012) Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice. Ann Rheum Dis 71:613–616PubMedGoogle Scholar
  113. 113.
    Zimmermann P, Boeuf S, Dickhut A, Boehmer S, Olek S, Richter W (2008) Correlation of COL10A1 induction during chondrogenesis of mesenchymal stem cells with demethylation of two CpG sites in the COL10A1 promoter. Arthritis Rheum 58:2743–2753PubMedGoogle Scholar
  114. 114.
    de Andres MC, Kingham E, Imagawa K, Gonzalez A, Roach HI, Wilson DI, Oreffo RO (2013) Epigenetic regulation during fetal femur development: DNA methylation matters. PLoS ONE 8:e54957PubMedGoogle Scholar
  115. 115.
    Bui C, Barter MJ, Scott JL, Xu Y, Galler M, Reynard LN, Rowan AD, Young DA (2012) cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis. FASEB J 26:3000–3011PubMedGoogle Scholar
  116. 116.
    Hashimoto K, Otero M, Imagawa K, de Andres MC, Coico JM, Roach HI, Oreffo RO, Marcu KB, Goldring MB (2013) Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1beta (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J Biol Chem 288:10061–10072PubMedGoogle Scholar
  117. 117.
    Kobayashi T, Lu J, Cobb BS, Rodda SJ, McMahon AP, Schipani E, Merkenschlager M, Kronenberg HM (2008) Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci USA 105:1949–1954PubMedGoogle Scholar
  118. 118.
    Lin EA, Kong L, Bai XH, Luan Y, Liu CJ (2009) miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1. J Biol Chem 284:11326–11335PubMedGoogle Scholar
  119. 119.
    Miyaki S, Sato T, Inoue A, Otsuki S, Ito Y, Yokoyama S, Kato Y, Takemoto F, Nakasa T, Yamashita S, Takada S, Lotz MK, Ueno-Kudo H, Asahara H (2010) MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev 24:1173–1185PubMedGoogle Scholar
  120. 120.
    Yang B, Guo H, Zhang Y, Chen L, Ying D, Dong S (2011) MicroRNA-145 regulates chondrogenic differentiation of mesenchymal stem cells by targeting Sox9. PLoS ONE 6:e21679PubMedGoogle Scholar
  121. 121.
    Dudek KA, Lafont JE, Martinez-Sanchez A, Murphy CL (2010) Type II collagen expression is regulated by tissue-specific miR-675 in human articular chondrocytes. J Biol Chem 285:24381–24387PubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Department of Bone and Mineral ResearchOsaka Medical Center and Research Institute for Maternal and Child HealthIzumiJapan

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