Current Osteoporosis Reports

, Volume 12, Issue 4, pp 439–445 | Cite as

Extracellular Matrix and Developing Growth Plate

  • Johanna MyllyharjuEmail author
Skeletal Development (E Schipani and E Zelzer, Section Editors)


Growth plate is a specialized cartilaginous structure that mediates the longitudinal growth of skeletal bones. It consists of ordered zones of chondrocytes that secrete an extracellular matrix (ECM) composed of specific types of collagens and proteoglycans. Several heritable human skeletal dysplasias are caused by mutations in these ECM components and this review focuses on the roles of type II, IX, X, and XI collagens, aggrecan, matrilins, perlecan, and cartilage oligomeric matrix protein in the growth plate as deduced from human disease phenotypes and mouse models. Substantial advances have been achieved in deciphering the interaction networks and individual roles of these components in the construction of the growth plate ECM. Furthermore, ER stress and other cellular responses have been identified as key downstream effects of the ECM mutations contributing to abnormal growth plate development. The next challenge is to utilize the molecular level knowledge for the development of potential therapeutics.


Growth plate Extracellular matrix Collagen Aggrecan Matrilin Perlecan Cartilage oligomeric matrix protein ER stress 


Compliance with Ethics Guidelines

Conflict of Interest

J. Myllyharju has received research grants from FibroGen Inc.

Human and Animal Rights and Informed Consent

All studies by the authors involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Aszódi A, Bateman JF, Gustafsson E, Boot-Handford R, Fässler R. Mammalian skeletogenesis and extracellular matrix: what can we learn from knockout mice? Cell Struct Funct. 2000;25:73–84.PubMedCrossRefGoogle Scholar
  2. 2.
    Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu Rev Cell Dev Biol. 2009;25:629–48.PubMedCrossRefGoogle Scholar
  3. 3.
    Michigami T. Regulatory mechanisms for the development of growth plate cartilage. Cell Mol Life Sci. 2013;70:4213–21.PubMedCrossRefGoogle Scholar
  4. 4.
    Mackie EJ, Tatarczuch L, Mirams M. The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification. J Endocrinol. 2011;211:109–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Tsang KY, Tsang WS, Chan D, Cheah KSE. The chondrocytic journey in endochondral bone growth and skeletal dysplasia. Birth Defects Res C Embryo Today. 2014;102:52–73.CrossRefGoogle Scholar
  6. 6.
    Eyre D. Collagen of articular cartilage. Arthritis Res. 2002;4:30–5.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kadler KE, Hill A, Canty-Laird EG. Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr Opin Cell Biol. 2008;20:495–501.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Schaefer L, Iozzo RV. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction. J Biol Chem. 2008;283:21305–9.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Heinegård D. Proteoglycans and more—from molecules to biology. Int J Exp Path. 2009;90:575–86.CrossRefGoogle Scholar
  10. 10.
    Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011;155:943–68.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Docheva D, Popov C, Alberton P, Aszodi A. Integrin signaling in skeletal development and function. Birth Defects Res C Embryo Today. 2014;102:13–36.PubMedCrossRefGoogle Scholar
  12. 12.
    Keene DR, Oxford JT, Morris NP. Ultrastructural localization of collagen types II, IX, and XI in the growth plate of human rib and fetal bovine epiphyseal cartilage: type XI collagen is restricted to thin fibrils. J Histochem Cytochem. 1995;43:967–79.PubMedCrossRefGoogle Scholar
  13. 13.
    Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004;20:33–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Gordon MK, Hahn RA. Collagens. Cell Tissue Res. 2010;339:247–57.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3:a004978.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Arnold WV, Fertala A. Skeletal diseases caused by mutations that affect collagen structure and function. Int J Biochem Cell Biol. 2013;45:1556–67.PubMedCrossRefGoogle Scholar
  17. 17.
    Li S-W, Prockop DJ, Helminen H, Fässler R, Lapveteläinen T, Kiraly K, et al. Transgenic mice with targeted inactivation of the Col2a1 gene for collagen II develop a skeleton with membranous and periosteal bone but no endochondral bone. Genes Dev. 1995;9:2821–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Aszódi A, Chan D, Hunziker E, Bateman JF, Fässler R. Collagen II is essential for the removal of the notochord and the formation of intervertebral discs. J Cell Biol. 1998;143:1399–412.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Garofalo S, Vuorio E, Metsäranta M, Rosati R, Toman D, Vaughan J, et al. Reduced amounts of cartilage collagen fibrils and growth plate anomalies in transgenic mice harboring a glycine-to-cysteine mutation in the mouse type II procollagen α1-chain gene. Proc Natl Acad Sci U S A. 1991;88:9648–52.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Vandenberg P, Khillan JS, Prockop DJ, Helminen H, Kontusaari S, Ala-Kokko L. Expression of a partially deleted gene of human type II procollagen (COL2A1) in transgenic mice produces a chondrodysplasia. Proc Natl Acad Sci U S A. 1991;88:7640–4.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Metsäranta M, Garofalo S, Decker G, Rintala M, de Crombrugghe B, Vuorio E. Chondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of proα1(II) collagen chain. J Cell Biol. 1992;118:203–12.PubMedCrossRefGoogle Scholar
  22. 22.
    Helminen HJ, Kiraly K, Pelttari A, Tammi MI, Vandenberg P, Pereira R, et al. An inbred line of transgenic mice expressing an internally deleted gene for type II procollagen (COL2A1). Young mice have a variable phenotype of a chondrodysplasia and older mice have osteoarthritic changes in joints. J Clin Invest. 1993;92:582–95.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Maddox BK, Garofalo S, Smith C, Keene DR, Horton WA. Skeletal development in transgenic mice expressing a mutation at Gly574Ser of type II collagen. Dev Dyn. 1997;208:170–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Pace JM, Li Y, Seegmiller RE, Teuscher C, Taylor BA, Olsen BR. Disproportionate micromelia (Dmm) in mice is caused by a mutation in the C-propeptide coding region of Col2a1. Dev Dyn. 1997;208:25–33.PubMedCrossRefGoogle Scholar
  25. 25.
    So CL, Kaluarachchi K, Tam PP, Cheah KS. Impact of mutations of cartilage matrix genes on matrix structure, gene activity and chondrogenesis. Osteoarthr Cartil. 2001;9(Suppl A):S160–73.PubMedGoogle Scholar
  26. 26.
    Arita M, Li SW, Kopen G, Adachi E, Jimenez SA, Fertala A. Skeletal abnormalities and ultrastructural changes of cartilage in transgenic mice expressing a collagen II gene (COL2A1) with a Cys for Arg-α1-519 substitution. Osteoarthr Cartil. 2002;10:808–15.PubMedCrossRefGoogle Scholar
  27. 27.
    Gaiser KG, Maddox BK, Bann JG, Boswell BA, Keene DR, Garofalo S, et al. Y-position collagen II mutation disrupts cartilage formation and skeletal development in a transgenic mouse model of spondyloepiphyseal dysplasia. J Bone Miner Res. 2002;17:39–47.PubMedCrossRefGoogle Scholar
  28. 28.
    Barbieri O, Astigiano S, Morini M, Tavella S, Schito A, Corsi A, et al. Depletion of cartilage collagen fibrils in mice carrying a dominant negative Col2a1 transgene affects chondrocyte differentiation. Am J Physiol Cell Physiol. 2003;285:C1504–12.PubMedCrossRefGoogle Scholar
  29. 29.
    Donahue LR, Chang B, Mohan S, Miyakoshi N, Wergedal JE, Baylink DJ, et al. A missense mutation in the mouse Col2a1 gene causes spondyloepiphyseal dysplasia congenita, hearing loss, and retinoschisis. J Bone Miner Res. 2003;18:1612–21.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Sahlman J, Pitkänen MT, Prockop DJ, Arita M, Li SW, Helminen HJ, et al. A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice. Arthritis Rheum. 2004;50:3153–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Li Y, Lacerda DA, Warman ML, Beier DR, Yoshioka H, Ninomiya Y, et al. A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell. 1995;80:423–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Nakata K, Ono K, Miyazaki J, Olsen BR, Muragaki Y, Adachi E, et al. Osteoarthritis associated with mild chondrodysplasia in transgenic mice expressing α1(IX) collagen chains with a central deletion. Proc Natl Acad Sci U S A. 1993;90:2870–4.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Fässler R, Schnegelsberg PNJ, Dausman J, Shinya T, Muragaki Y, McCarthy MT, et al. Mica Lacking α(IX) collagen develop noninflammatory degenerative joint disease. Proc Natl Acad Sci U S A. 1994;91:5070–4.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Hagg R, Hedbom E, Möllers U, Aszódi A, Fässler R, Bruckner P. Absence of the alpha1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice. J Biol Chem. 1997;272:20650–4.PubMedCrossRefGoogle Scholar
  35. 35.
    Dreier R, Opolka A, Grifka J, Bruckner P, Grässel S. Collagen IX-deficiency seriously compromises growth cartilage development in mice. Matrix Biol. 2008;27:319–29.PubMedCrossRefGoogle Scholar
  36. 36.
    Jacenko O, LuValle PA, Olsen BR. Spondylometaphyseal dysplasia in mice carrying a dominant negative mutation in a matrix protein specific for cartilage-to-bone transition. Nature. 1993;365:56–61.PubMedCrossRefGoogle Scholar
  37. 37.
    Jacenko O, LuValle P, Solum K, Olsen BR. A dominant negative mutation in the α1(X) collagen gene produces spondylometaphyseal defects in mice. Prog Clin Biol Res. 1993;383B:427–36.PubMedGoogle Scholar
  38. 38.
    Rosati R, Horan GSB, Pinero GJ, Garofalo S, Keene DR, Horton WA, et al. Normal long bone growth and development in type X collagen-null mice. Nat Genet. 1994;8:129–35.PubMedCrossRefGoogle Scholar
  39. 39.
    Kwan KM, Pang MKM, Zhou S, Cowan SK, Kong RYC, Pfordte T, et al. Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function. J Cell Biol. 1997;136:459–71.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Gress CJ, Jacenko O. Growth plate compressions and altered hematopoiesis in collagen X null mice. J Cell Biol. 2000;149:983–93.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Ho MS, Tsang KY, Lo RL, Susic M, Mäkitie O, Chan TW, et al. COL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid. Hum Mol Genet. 2007;16:1201–15.PubMedCrossRefGoogle Scholar
  42. 42.
    Tsang KY, Chan D, Cheslett D, Chan WC, So CL, Melhado IG, et al. Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLoS Biol. 2007;5:e44.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Rajpar MH, McDermott B, Kung L, Eardley R, Knowles L, Heeran M, et al. Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet. 2009;5:e1000691.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Watanabe H, Kimata K, Line S, Strong D, Gao L-Y, Kozak CA, et al. Mouse cartilage matrix deficiency (CMD) caused by a 7 bp deletion in the aggrecan gene. Nat Genet. 1994;7:154–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Wai AWK, Ng LJ, Watanabe H, Yamada Y, Tam PPL, Cheah KSE. Disrupted expression of matrix genes in the growth plate of the mouse cartilage matrix deficiency (CMD) mutant. Dev Genet. 1998;22:349–58.PubMedCrossRefGoogle Scholar
  46. 46.
    Klatt AR, Becker AK, Neacsu CD, Paulsson M, Wagener R. The matrilins: modulators of extracellular matrix assembly. Int J Biochem Cell Biol. 2011;43:320–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Aszódi A, Bateman JF, Hirsch E, Baranyi M, Hunziker EB, Hauser N, et al. Normal skeletal development of mice lacking matrilin 1: redundant function of matrilins in cartilage? Mol Cell Biol. 1999;19:7841–5.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Ko Y, Kobbe B, Nicolae C, Miosge N, Paulsson M, Wagenere R, et al. Matrilin-3 is dispensable for mouse skeletal growth and development. Mol Cell Biol. 2004;24:1691–9.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Mates L, Nicolae C, Morgelin M, Deak F, Kiss I, Aszódi A. Mice lacking the extracellular matrix adaptor protein matrilin-2 develop without obvious abnormalities. Matrix Biol. 2004;23:195–204.PubMedCrossRefGoogle Scholar
  50. 50.
    Huang X, Birk DE, Goetinck PF. Mice lacking matrilin-1 (cartilage matrix protein) have alterations in type II collagen fibrillogenesis and fibril organization. Dev Dyn. 1999;216:434–41.PubMedCrossRefGoogle Scholar
  51. 51.
    van der Weyden L, Wei L, Luo J, Yang X, Birk DE, Adams DJ, et al. Functional knockout of the matrilin-3 gene causes premature chondrocyte maturation to hypertrophy and increases bone mineral density and osteoarthritis. Am J Pathol. 2006;169:515–27.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Nicolae C, Ko Y-P, Miosge N, Niehoff A, Studer D, Enggist L, et al. Abnormal collagen fibrils in cartilage of matrilin-1/matrilin-3-deficient mice. J Biol Chem. 2007;282:22163–75.PubMedCrossRefGoogle Scholar
  53. 53.
    Leighton MP, Nundlaa S, Starborg T, Meadows RS, Suleman F, Knowles L, et al. Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation. Hum Mol Genet. 2007;16:1728–41.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Nundlall S, Rajpar MH, Bell PA, Clowes C, Zeeff LAH, Gardner B, et al. An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia. Cell Stress Chaperones. 2010;15:835–49.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Bell PA, Piróg KA, Fresquet M, Thornton DJ, Boot-Handford R, Briggs MD. Loss of matrilin 1 does not exacerbate the skeletal phenotype in a mouse model of multiple epiphyseal dysplasia caused by a Matn3 V194D mutation. Arthritis Rheum. 2012;64:1529–39.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Iozzo RV. Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol. 2005;6:646–56.PubMedCrossRefGoogle Scholar
  57. 57.
    Knox SM, Whitelock JM. Perlecan: how does one molecule do so many things? Cell Mol Life Sci. 2006;63:2435–45.PubMedCrossRefGoogle Scholar
  58. 58.
    Kruegel J, Miosge N. Basement membrane components are key players in specialized extracellular matrices. Cell Mol Life Sci. 2010;67:2879–95.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y. Perlecan is essential for cartilage and cephalic development. Nat Genet. 1999;23:354–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, et al. Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol. 1999;147:1109–22.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kvist AJ, Johnson AE, Mörgelin M, Gustafsson E, Bengtsson E, Lindblom K, et al. Chondroitin sulfate perlecan enhances collagen fibril formation. Implications for perlecan chondrodysplasias. J Biol Chem. 2006;281:33127–39.PubMedCrossRefGoogle Scholar
  62. 62.
    Rodgers KD, Sasaki T, Aszodi A, Jacenko O. Reduced perlecan in mice results in chondrodysplasia resembling Schwartz-Jampel syndrome. Hum Mol Genet. 2007;16:515–28.PubMedCrossRefGoogle Scholar
  63. 63.
    Lowe DA, Lepori-Bui N, Fomin PV, Sloofman LG, Zhou X, Farach-Carson MC, et al. Deficiency in perlecan/HSPG2 during bone development enhances osteogenesis and decreases quality of adult bone in mice. Calcif Tissue Int. 2014;95:29–38.PubMedCrossRefGoogle Scholar
  64. 64.
    Ishijima M, Suzuki N, Hozumi K, Matsunobu T, Kosaki K, Kaneko H, et al. Perlecan modulates VEGF signaling and is essential for vascularization in endochondral bone formation. Matrix Biol. 2012;31:234–45.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Posey KL, Alcorn JL, Hecth JT. Pseudoachondroplasia/COMP—translating from the bench to the bedside. Matrix Biol. 2014. doi: 10.1016/j.matbio.2014.05.006.
  66. 66.
    Hecht JT, Hayes E, Haynes R, Cole WG. COMP mutations, chondrocyte function and cartilage matrix. Matrix Biol. 2005;23:525–33.PubMedCrossRefGoogle Scholar
  67. 67.
    Svensson L, Aszódi A, Heinegård D, Hunziker EB, Reinholt FP, Fässler R, et al. Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol Cell Biol. 2002;22:4366–71.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Blumbach K, Niehoff A, Paulsson M, Zaucke F. Ablation of collagen IX and COMP disrupts epiphyseal cartilage architecture. Matrix Biol. 2008;27:306–18.PubMedCrossRefGoogle Scholar
  69. 69.
    Schmitz M, Niehoff A, Miosge N, Smyth N, Paulsson M, Zaucke F. Transgenic mice expressing D469Δ mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations. Matrix Biol. 2008;27:67–85.PubMedCrossRefGoogle Scholar
  70. 70.
    Suleman F, Gualeni B, Gregson HJ, Leighton MP, Piróg KA, Edwards S, et al. A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. Hum Mutat. 2012;33:218–31.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Piróg-Garcia KA, Meadows RS, Knowles L, Heinegård D, Thornton DJ, Kadler KE, et al. Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Hum Mol Genet. 2007;16:2072–88.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Posey KL, Veerisetty AC, Liu P, Wang HR, Poindexter BJ, Bick R, et al. An inducible cartilage oligomeric matrix protein mouse model recapitulates human pseudoachondroplasia phenotype. Am J Pathol. 2009;175:1555–63.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Posey KL, Coustry F, Veerisetty AC, Liu P, Alcorn JL, Hecht JT. Chop (Ddit3) is essential for D469del-COMP retention and cell death in chondrocytes in an inducible transgenic mouse model of pseudoachondroplasia. Am J Pathol. 2012;180:727–37.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Posey KL, Coustry F, Veerisetty AC, Liu P, Alcorn JL, Hecht JT. Chondrocyte-specific pathology during skeletal growth and therapeutics in a murine model of pseudoachondroplasia. J Bone Miner Res. 2014;29:1258–68.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Tsang KY, Chan D, Bateman JF, Cheah KS. In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences. J Cell Sci. 2010;123:2145–54.PubMedCrossRefGoogle Scholar
  76. 76.
    Bentovim L, Amarilio R, Zelzer E. HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development. Development. 2012;139:4473–83.PubMedCrossRefGoogle Scholar
  77. 77.••
    Gualeni B, Rajpar MH, Kellogg A, Bell PA, Arvan P, Boot-Handford RP, et al. A novel transgenic mouse model of growth plate dysplasia reveals the decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth. Dis Model Mech. 2013;6:1414–25. The report shows that ER stress independent of ECM mutations is a key contributor in abnormal skeletogenesis.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular MedicineUniversity of OuluOuluFinland

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