Basic Components of Connective Tissues and Extracellular Matrix: Elastin, Fibrillin, Fibulins, Fibrinogen, Fibronectin, Laminin, Tenascins and Thrombospondins

  • Jaroslava HalperEmail author
  • Michael Kjaer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 802)


Collagens are the most abundant components of the extracellular matrix and many types of soft tissues. Elastin is another major component of certain soft tissues, such as arterial walls and ligaments. Many other molecules, though lower in quantity, function as essential components of the extracellular matrix in soft tissues. Some of these are reviewed in this chapter. Besides their basic structure, biochemistry and physiology, their roles in disorders of soft tissues are discussed only briefly as most chapters in this volume deal with relevant individual compounds. Fibronectin with its muldomain structure plays a role of “master organizer” in matrix assembly as it forms a bridge between cell surface receptors, e.g., integrins, and compounds such collagen, proteoglycans and other focal adhesion molecules. It also plays an essential role in the assembly of fibrillin-1 into a structured network. Laminins contribute to the structure of the extracellular matrix (ECM) and modulate cellular functions such as adhesion, differentiation, migration, stability of phenotype, and resistance towards apoptosis. Though the primary role of fibrinogen is in clot formation, after conversion to fibrin by thrombin, it also binds to a variety of compounds, particularly to various growth factors, and as such fibrinogen is a player in cardiovascular and extracellular matrix physiology. Elastin, an insoluble polymer of the monomeric soluble precursor tropoelastin, is the main component of elastic fibers in matrix tissue where it provides elastic recoil and resilience to a variety of connective tissues, e.g., aorta and ligaments. Elastic fibers regulate activity of TGFβs through their association with fibrillin microfibrils. Elastin also plays a role in cell adhesion, cell migration, and has the ability to participate in cell signaling. Mutations in the elastin gene lead to cutis laxa. Fibrillins represent the predominant core of the microfibrils in elastic as well as non-elastic extracellular matrixes, and interact closely with tropoelastin and integrins. Not only do microfibrils provide structural integrity of specific organ systems, but they also provide a scaffold for elastogenesis in elastic tissues. Fibrillin is important for the assembly of elastin into elastic fibers. Mutations in the fibrillin-1 gene are closely associated with Marfan syndrome. Fibulins are tightly connected with basement membranes, elastic fibers and other components of extracellular matrix and participate in formation of elastic fibers. Tenascins are ECM polymorphic glycoproteins found in many connective tissues in the body. Their expression is regulated by mechanical stress both during development and in adulthood. Tenascins mediate both inflammatory and fibrotic processes to enable effective tissue repair and play roles in pathogenesis of Ehlers-Danlos, heart disease, and regeneration and recovery of musculo-tendinous tissue. One of the roles of thrombospondin 1 is activation of TGFβ. Increased expression of thrombospondin and TGFβ activity was observed in fibrotic skin disorders such as keloids and scleroderma. Cartilage oligomeric matrix protein (COMP) or thrombospondin-5 is primarily present in the cartilage. High levels of COMP are present in fibrotic scars and systemic sclerosis of the skin, and in tendon, especially with physical activity, loading and post-injury. It plays a role in vascular wall remodeling and has been found in atherosclerotic plaques as well.


Elastin Fibrillin Fibulins Laminin Tenascins 


  1. 1.
    Kjaer M (2004) Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol Rev 84:649–698PubMedGoogle Scholar
  2. 2.
    Leahy DJ, Aukhil I, Erickson HP (1996) 2.0 A crystal structure of a four-domain segment of human fibronectin encompassing the RGD loop and synergy region. Cell 84:155–164PubMedGoogle Scholar
  3. 3.
    Potts JR, Campbell ID (1994) Fibronectin structure and assembly. Curr Opin Cell Biol 6:648–655PubMedGoogle Scholar
  4. 4.
    Sabatier L, Chen D, Fagotto-Kaufmann C, Hubmacher D, McKee MD, Annis DS, Mosher DF, Reinhardt DP (2009) Fibrillin assembly requires fibronectin. Mol Biol Cell 20:846–858PubMedCentralPubMedGoogle Scholar
  5. 5.
    Mao Y, Schwarzbauer J (2005) Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol 24:389–399PubMedGoogle Scholar
  6. 6.
    Takahashi S, Leiss M, Moser M, Ohashi T, Kitao T, Heckmann D, Pfeifer A, Kessler H, Takagi J, Erickson HP, Fässler R (2007) The RGD motif in fibronectin is essential for development but dispensable for fibril assembly. J Cell Biol 178:167–178PubMedGoogle Scholar
  7. 7.
    Singh P, Schwarzbauer JE (2012) Fibronectin and stem cell differentiation – lessons from chondrogenesis. J Cell Sci 125:3703–3712PubMedGoogle Scholar
  8. 8.
    Dallas SL, Chen Q, Sivakumar P (2006) Dynamics of assembly and reorganization of extracellular matrix proteins. Curr Top Dev Biol 75:1–24PubMedGoogle Scholar
  9. 9.
    Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Jones JCR, Kleinman HK, Marinkovich MP, Martin GR, Mayer U, Meneguzzi G, Miner JH, Miyazaki M, Patarroyo M, Paulsson M, Quaranta V, Sanes JR, Sasaki T, Sekiguchi K, Sorokin LM, Talts JF, Tryggvason K, Uitto J, Virtanen I, von der Mark K, Wewer UM, Yamada Y, Yurchenco PD (2005) A simplified laminin nomenclature. Matrix Biol 24:326–332PubMedGoogle Scholar
  10. 10.
    Miner JH, Yurchenco PD (2004) Laminin functions in tissue morphogenesis. Annu Rev Cell Dev Biol 20:255–284PubMedGoogle Scholar
  11. 11.
    Domogatskaya A, Rodin S, Tryggvason K (2012) Functional diversity of laminins. Annu Rev Cell Dev Biol 28:523–553PubMedGoogle Scholar
  12. 12.
    MacDonald PR, Lustig A, Steinmetz MO, Kammerer RA (2010) Laminin chain assembly is regulated by specific coiled-coil interactions. J Struct Biol 170:398–405PubMedCentralPubMedGoogle Scholar
  13. 13.
    Grounds MD, Sorokin L, White J (2005) Strength at the extracellular matrix-muscle interface. Scand J Med Sci Sports 15:381–391PubMedGoogle Scholar
  14. 14.
    Taylor SH, Al-Youha S, Van Agtmael T, Lu Y, Wong J, McGrouther DA, Kadler KE (2011) Tendon is covered by a basement membrane epithelium that is required for cell retention and the prevention of adhesion formation. PLoS One 6:e16337PubMedCentralPubMedGoogle Scholar
  15. 15.
    Molloy TJ, de Bock CE, Wang Y, Murrell GA (2006) Gene expression changes in SNAP-stimulated and iNOS-transfected tenocytes–expression of extracellular matrix genes and its implications for tendon-healing. J Orthop Res 24:1869–1882PubMedGoogle Scholar
  16. 16.
    Sato N, Nakamura M, Chikama T, Nishida T (1999) Abnormal deposition of laminin and type IV collagen at corneal epithelial basement membrane during wound healing in diabetic rats. Jpn J Ophthalmol 43:343–347PubMedGoogle Scholar
  17. 17.
    Della Corte A, De Santo LS, Montagnani S, Quarto C, Romano G, Amarelli C, Scardone M, De Feo M, Cotrufo M, Caianiello G (2006) Spatial patterns of matrix protein expression in dilated ascending aorta with aortic regurgitation: congenital bicuspid valve versus Marfan’s syndrome. J Heart Valve Dis 15:20–27PubMedGoogle Scholar
  18. 18.
    Fish RJ, Neerman-Arbez M (2012) Fibrinogen gene regulation. Thromb Haemost 108:419–426PubMedGoogle Scholar
  19. 19.
    Doolittle RF, Goldbaum DM, Doolittle LR (1978) Designation of sequences involved in the “coiled-coil” interdominal connections in fibrinogen: constructions of an atomic scale model. J Mol Biol 120:311–325PubMedGoogle Scholar
  20. 20.
    Ariens RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ (2002) Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 100:743–754PubMedGoogle Scholar
  21. 21.
    Cilia La Corte AL, Philippou H, Ariëns RA (2011) Role of fibrin structure in thrombosis and vascular disease. Adv Protein Chem Struct Biol 83:75–127PubMedGoogle Scholar
  22. 22.
    Sahni A, Francis CW (2000) Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation. Blood 96:3772–3778PubMedGoogle Scholar
  23. 23.
    Sahni A, Odrljin T, Francis CW (1998) Binding of basic fibroblast growth factor to fibrinogen and fibrin. J Biol Chem 273:7554–7559PubMedGoogle Scholar
  24. 24.
    Clark RA, Lanigan JM, DellaPelle P, Manseau E, Dvorak HF, Colvin RB (1982) Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol 79:264–269PubMedGoogle Scholar
  25. 25.
    Donaldson DJ, Mahan JT, Amrani D, Hawiger J (1989) Fibrinogen-mediated epidermal cell migration: structural correlates for fibrinogen function. J Cell Sci 94:101–108PubMedGoogle Scholar
  26. 26.
    Armstrong PC, Peter K (2012) GPIIb/IIIa inhibitors: from bench to bedside and back to bench again. Thromb Haemost 107:808–814PubMedGoogle Scholar
  27. 27.
    Muiznieks LD, Weiss AS, Keeley FW (2010) Structural disorder and dynamics of elastin. Biochem Cell Biol 88:239–250PubMedGoogle Scholar
  28. 28.
    Mithieux SM, Wise SG, Weiss AS (2013) Tropoelastin – a multifaceted naturally smart material. Adv Drug Deliv Rev 65:421–428PubMedGoogle Scholar
  29. 29.
    Kielty CM (2006) Elastic fibres in health and disease. Expert Rev Mol Med 8:1–23PubMedGoogle Scholar
  30. 30.
    Csiszar K (2001) Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol 70:1–32PubMedGoogle Scholar
  31. 31.
    Lee JE, Kim Y (2006) A tissue-specific variant of the human lysyl oxidase-like protein 3 (LOXL3) functions as an amine oxidase with substrate specificity. J Biol Chem 281:37282–37290PubMedGoogle Scholar
  32. 32.
    Kim YM, Kim EC, Kim Y (2011) The human lysyl oxidase-like 2 protein functions as an amine oxidase toward collagen and elastin. Mol Biol Rep 38:145–149PubMedGoogle Scholar
  33. 33.
    Hinek A, Rabinovitch M (1994) 67-kD elastin-binding protein is a protective “companion” of extracellular insoluble elastin and intracellular tropoelastin. J Cell Biol 126:563–574PubMedGoogle Scholar
  34. 34.
    Yeo GC, Keeley FW, Weiss AS (2011) Coacervation of tropoelastin. Adv Colloid Interface Sci 167:94–103PubMedGoogle Scholar
  35. 35.
    Kozel BA, Rongish BJ, Czirok A, Zach J, Little CD, Davis EC, Knutsen RH, Wagenseil JE, Levy MA, Mecham RP (2006) Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. J Cell Physiol 207:87–96PubMedGoogle Scholar
  36. 36.
    Berk DR, Bentley DD, Bayliss SJ, Lind A, Urban Z (2012) Cutis laxa: a review. J Am Acad Dermatol 66:842.e1–842.e17Google Scholar
  37. 37.
    Baccarani-Contri M, Vincenzi D, Cicchetti F, Mori G, Pasquali-Ronchetti I (1990) Immunocytochemical localization of proteoglycans within normal elastin fibers. Eur J Cell Biol 53:305–312PubMedGoogle Scholar
  38. 38.
    Gheduzzi D, Guerra D, Bochicchio B, Pepe A, Tamburro AM, Quaglino D, Mithieux S, Weiss AS, Pasquali Ronchetti I (2005) Heparan sulphate interacts with tropoelastin, with some tropoelastin peptides and is present in human dermis elastic fibers. Matrix Biol 24:15–25PubMedGoogle Scholar
  39. 39.
    Kozel BA, Ciliberto CH, Mecham RP (2004) Deposition of tropoelastin into the extracellular matrix requires a competent elastic fiber scaffold but not live cells. Matrix Biol 23:23–34PubMedGoogle Scholar
  40. 40.
    Wagenseil JE, Mecham RP (2012) Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res 5:264–273PubMedCentralPubMedGoogle Scholar
  41. 41.
    Mithieux SM, Weiss AS (2005) Elastin. Adv Protein Chem 70:437–461PubMedGoogle Scholar
  42. 42.
    Chung MI, Miao M, Stahl RJ, Chan E, Parkinson J, Keeley FW (2006) Sequences and domain structures of mammalian, avian, amphibian, and teleost tropoelastins: clues to the evolutionary history of elastin. Matrix Biol 25:495–504Google Scholar
  43. 43.
    Karnik SK, Brooke BS, Bayes-Genis A, Sorensen L, Wythe JD, Schwartz RS, Keating MT, Li DY (2003) A critical role for elastin signaling in vascular morphogenesis and disease. Development 130:411–423PubMedGoogle Scholar
  44. 44.
    Mecham RP (1998) Overview of extracellular matrix. In: Current protocols in cell biology. Wiley, New YorkGoogle Scholar
  45. 45.
    Fung YC (1993) Biomechanics: mechanical properties of living tissues, 2nd edn. Springer, New YorkGoogle Scholar
  46. 46.
    Wagenseil JE, Mecham RP (2009) Vascular extracellular matrix and arterial mechanics. Physiol Rev 89:957–989PubMedCentralPubMedGoogle Scholar
  47. 47.
    Kostrominova TY, Brooks SV (2013) Age-related changes in structure and extracellular matrix protein expression levels in rat tendons. Age 35:2203–2214Google Scholar
  48. 48.
    Greenwald SJ (2008) Ageing of the conduit arteries. J Pathol 211:157–172Google Scholar
  49. 49.
    Li Z, Froehlich J, Galis ZS, Lakatta EG (1999) Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats. Hypertension 33:116–123PubMedGoogle Scholar
  50. 50.
    Tamarina NA, McMillan WD, Shively VP, Pearce WH (1999) Expression of matrix metalloproteinases and their inhibitors in anuerysm and normal aorta. Surgery 122:264–271Google Scholar
  51. 51.
    Allaire E, Forough R, Clowes M, Starcher B, Clowes AW (1998) Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest 102:1413–1420PubMedCentralPubMedGoogle Scholar
  52. 52.
    Jiang L, Wang M, Zhang J, Monticone RE, Telljohann R, Spinnetti G, Pintus G, Lakatta EG (2008) Increased calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells. PLoS One 3:e2231PubMedCentralPubMedGoogle Scholar
  53. 53.
    Castro MM, Rizzi E, Figueiredo-Lopes L, Fernandes K, Bendhack LM, Pitol DL, Gerlach RF, Tanus-Santos JE (2008) Metalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. Atherosclerosis 198:320–331PubMedGoogle Scholar
  54. 54.
    Wolinsky H (1970) Response of the rat aortic media to hypertension. Morphological and chemical studies. Circ Res 26:507–522PubMedGoogle Scholar
  55. 55.
    Todorovich-Hunter L, Johnson D, Ranger P, Keeley F, Rabinovitch M (1988) Altered elastin and collagen synthesis associated with progressive pulmonary hypertension induced by monocrotaline. A biochemical and ultrastructural study. Lab Invest 58:184–195PubMedGoogle Scholar
  56. 56.
    O’Connor WN, Davis JB Jr, Geissler R, Cottrill CM, Noonan JA, Todd EP (1985) Supravalvular aortic stenosis. Clinical and pathological observations in six patients. Arch Pathol Lab Med 109:179–185PubMedGoogle Scholar
  57. 57.
    Urban Z, Michels VV, Thibodeau SN, Davis EC, Bonnefont J-P, Munnich A, Eyskens B, Gewillig M, Devriendt K, Boyd CD (2000) Isolated supravalvular aortic stenosis: functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay. Hum Genet 106:577–588PubMedGoogle Scholar
  58. 58.
    Rodriguez-Revenga L, Iranzo P, Badenas C, Puig S, Carrio A, Mila M (2004) A novel elastin gene mutation resulting in an autosomal dominant from of cutis laxa. Arch Dermatol 149:1135–1139Google Scholar
  59. 59.
    Tassabehji M, Metcalfe K, Hurst J, Ashcroft GS, Kielty C, Wilmot C, Donnai D, Read AP, Jones CJP (1998) An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autodomal dominant cutis laxa. Hum Mol Genet 7:1021–1028PubMedGoogle Scholar
  60. 60.
    Li DY, Brooke D, Davis EC, Mecham RP, Sorensen LK, Boak KK, Eichwald E, Keating MT (1998) Elastin is an essential determinant of arterial morphogenesis. Nature 393:276–289PubMedGoogle Scholar
  61. 61.
    Faury G, Pezet M, Knutsen RH, Boyle WA, Heximer SP, MacLean SE, Minkes RK, Blumer KJ, Kovacs A, Kelly DP, Li DY, Starcher B, Mecham RP (2003) Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest 112:1419–1428PubMedCentralPubMedGoogle Scholar
  62. 62.
    Schwill S, Seppelt P, Grünhagen J, Ott CE, Jugold M, Ruhparwar A, Robinson PN, Karck M, Kallenbach K (2013) The fibrillin-1 hypomorphic mgR/mgR murine model of Marfan syndrome shows severe elastolysis in all segments of the aorta. J Vasc Surg 57:1628–1636PubMedGoogle Scholar
  63. 63.
    Kielty CM, Sherratt MJ, Marson A, Baldock C (2005) Fibrillin microfibrils. Adv Protein Chem 70:405–436PubMedGoogle Scholar
  64. 64.
    Zhang H, Apfelroth SD, Hu W, Davis EC, Sanguineti C, Bonadio J, Mecham RP, Ramirez F (1994) Structure and expression of fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices. J Cell Biol 124:855–863PubMedGoogle Scholar
  65. 65.
    Charbonneau NL, Dzamba BJ, Ono RN, Keene DR, Corson GM, Reinhardt DP, Sakai LY (2003) Fibrillins can co-assemble in fibrils, but fibrillin fibril composition displays cell-specific differences. J Biol Chem 278:2740–2749PubMedGoogle Scholar
  66. 66.
    Cain SA, Morgan A, Sherratt MJ, Ball SG, Shuttleworth CA, Kielty CM (2006) Proteomic analysis of fibrillin-rich microfibrils. Proteomics 6:111–122PubMedGoogle Scholar
  67. 67.
    Robinson PN, Arteaga-Solis E, Baldock C, Collod-Béroud G, Booms P, De Paepe A, Dietz HC, Guo G, Handford PA, Judge DP, Kielty CM, Loeys B, Milewicz DM, Ney A, Ramirez F, Reinhardt DP, Tiedemann K, Whiteman P, Godfrey M (2006) The molecular genetics of Marfan syndrome and related disorders. J Med Genet 43:769–787PubMedGoogle Scholar
  68. 68.
    Milewicz DM, Grossfield J, Cao SN, Kielty C, Covitz W, Jewett T (1995) A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. J Clin Invest 95:2373–2378PubMedCentralPubMedGoogle Scholar
  69. 69.
    Raghunath M, Putnam EA, Ritty T, Hamstra D, Park ES, Tschodrich-Rotter M, Peters P, Rehemtulla A, Milewicz DM (1999) Carboxy-terminal conversion of profibrillin to fibrillin at a basic site by PACE/furin-like activity required for incorporation in the matrix. J Cell Sci 112:1093–1100PubMedGoogle Scholar
  70. 70.
    Hubmacher D, Sabatier L, Annis DS, Mosher DF, Reinhardt DP (2011) Homocysteine modifies structural and functional properties of fibronectin and interferes with the fibronectin-fibrillin-1 interaction. Biochemistry 50:5322–5332PubMedCentralPubMedGoogle Scholar
  71. 71.
    Yanagisawa H, Davis EC (2010) Unraveling the mechanism of elastic fiber assembly: the roles of short fibulins. Int J Biochem Cell Biol 42:1084–1093PubMedCentralPubMedGoogle Scholar
  72. 72.
    Wachi H, Nonaka R, Sato F, Shibata-Sato K, Ishida M, Iketani S, Maeda I, Okamoto K, Urban Z, Onoue S, Seyama Y (2008) Characterization of the molecular interaction between tropoelastin and DANCE/fibulin-5. J Biochem 143:633–639PubMedGoogle Scholar
  73. 73.
    Hambleton S, Valeyev NV, Muranyi A, Knott V, Werner JM, McMichael AJ, Handford PA, Downing AK (2004) Structural and functional properties of the human notch-1 ligand binding region. Structure 12:2173–2183PubMedGoogle Scholar
  74. 74.
    Yanagisawa H, Schluterman MK, Brekken RA (2009) Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. J Cell Commun Signal 3:337–347PubMedCentralPubMedGoogle Scholar
  75. 75.
    Zheng Q, Davis EC, Richardson JA, Starcher BC, Li T, Gerard RD, Yanagisawa H (2007) Molecular analysis of fibulin-5 function during de novo synthesis of elastic fibers. Mol Cell Biol 27:1083–1095PubMedCentralPubMedGoogle Scholar
  76. 76.
    Hirai M, Ohbayashi T, Horiguchi M, Okawa K, Hagiwara A, Chien KR, Kita T, Nakamura T (2007) Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo. J Cell Biol 176:1061–1071PubMedGoogle Scholar
  77. 77.
    Liu X, Zhao Y, Gao J, Pawlyk B, Starcher B, Spencer JA, Yanagisawa H, Zuo J, Li T (2004) Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 36:178–182PubMedGoogle Scholar
  78. 78.
    Horiguchi M, Inoue T, Ohbayashi T, Hirai M, Noda K, Marmorstein LY, Yabe D, Takagi K, Akama TO, Kita T, Kimura T, Nakamura T (2009) Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. Proc Natl Acad Sci U S A 106:19029–19034PubMedCentralPubMedGoogle Scholar
  79. 79.
    Sato F, Wachi H, Ishida M, Nonaka R, Onoue S, Urban Z, Starcher BC, Seyama Y (2007) Distinct steps of cross-linking, self-association, and maturation of tropoelastin are necessary for elastic fiber formation. J Mol Biol 369:841–851PubMedGoogle Scholar
  80. 80.
    Klenotic PA, Munier FL, Marmorstein LY, Anand-Apte B (2004) Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1): implications for macular degenerations. J Biol Chem 279:30469–30473PubMedGoogle Scholar
  81. 81.
    Ramirez F, Dietz HC (2007) Fibrillin-rich microfibrils: structural determinants of morphogenetic and homeostatic events. J Cell Physiol 213:326–330PubMedGoogle Scholar
  82. 82.
    DeVega A, Iwamoto T, Yamada Y (2009) Fibulins: multiple roles in matrix structures and tissue functions. Cell Mol Life Sci 66:1890–1902Google Scholar
  83. 83.
    Zhang HY, Timpl R, Sasaki T, Chu ML, Ekblom P (1996) Fibulin-1 and fibulin-2 expression during organogenesis in the developing mouse embryo. Dev Dyn 205:348–364PubMedGoogle Scholar
  84. 84.
    Tsuda T, Wang H, Timpl R, Chu ML (2001) Fibulin-2 expression marks transformed mesenchymal cells in developing cardiac valves, aortic arch vessels and coronary vessels. Dev Dyn 222:89–100PubMedGoogle Scholar
  85. 85.
    Tucker RP, Drabikowski K, Hess JF, Ferralli J, Chiquet-Ehrismann R, Adams JC (2006) Phylogenetic analysis of the tenascin gene family: evidence of origin early in the chordate lineage. BMC Evol Biol 6:60PubMedCentralPubMedGoogle Scholar
  86. 86.
    Tucker RP, Chiquet-Ehrismann R (2009) The regulation of tenascin expression by tissue microenvironments. Biochim Biophys Acta 1793:888–892PubMedGoogle Scholar
  87. 87.
    Okamoto H, Imanaka-Yoshida K (2012) Matricellular proteins: new molecular targets to prevent heart failure. Cardiovasc Ther 30:e198–e209PubMedGoogle Scholar
  88. 88.
    Chiquet-Ehrismann R, Kalla P, Pearson CA, Beck K, Chiquet M (1988) Tenascin interferes with fibronectin action. Cell 53:383–390PubMedGoogle Scholar
  89. 89.
    Huang W, Chiquet-Ehrismann R, Moyano JV, Garcia-Pardo V, Orend G (2001) Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation. Cancer Res 61:8586–8594PubMedGoogle Scholar
  90. 90.
    Midwood KS, Schwarzbauer JS (2002) Tenascin-C modulates matrix contraction via focal adhesion kinase- and Rho-mediated signaling pathways. Mol Biol Cell 13:3601–3613PubMedCentralPubMedGoogle Scholar
  91. 91.
    Chiquet-Ehrismann R, Chiquet M (2003) Regulation and putative functions during pathological stress. J Pathol 200:488–499PubMedGoogle Scholar
  92. 92.
    Jones FS, Jones PL (2000) The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling. Dev Dyn 218:235–259PubMedGoogle Scholar
  93. 93.
    Kreja L, Liedert A, Schlenker H, Brenner RE, Fiedler J, Friemert B, Dürselen L, Ignatius A (2012) Effects of mechanical strain on human mesenchymal stem cells and ligament fibroblasts in a textured poly(L-lactide) scaffold for ligament tissue engineering. J Mater Sci Mater Med 23:2575–2582PubMedGoogle Scholar
  94. 94.
    Järvinen TA, Józsa L, Kannus P, Järvinen TL, Hurme T, Kvist M, Pelto-Huikko M, Kalimo H, Järvinen M (2003) Mechanical loading regulates the expression of tenascin-C in the myotendinous junction and tendon but does not induce de novo synthesis in the skeletal muscle. J Cell Sci 116:857–866PubMedGoogle Scholar
  95. 95.
    Mackie EJ, Scott-Burden T, Hahn AW, Kern F, Bernhardt J, Regenass S, Weller A, Bühler FR (1992) Expression of tenascin by vascular smooth muscle cells. Alterations in hypertensive rats and stimulation by angiotensin II. Am J Pathol 141:377–388PubMedGoogle Scholar
  96. 96.
    Page TH, Charles PJ, Piccinini AM, Nicolaidou V, Taylor PC, Midwood KS (2012) Raised circulating tenascin-C in rheumatoid arthritis. Arthritis Res Ther 14:R260PubMedCentralPubMedGoogle Scholar
  97. 97.
    Chockalingam PS, Glasson SS, Lohmander LS (2013) Tenascin-C levels in synovial fluid are elevated after injury to the human and canine joint and correlate with markers of inflammation and matrix degradation. Osteoarthritis Cartilage 21:339–345PubMedGoogle Scholar
  98. 98.
    Imanaka-Yoshida K (2012) Tenascin-C in cardiovascular tissue remodeling: from development to inflammation and repair. Circ J 76:2513–2520PubMedGoogle Scholar
  99. 99.
    Midwood KS, Hussenet T, Langlois B, Orend G (2011) Advances in tenascin-C biology. Cell Mol Life Sci 68:3175–3199PubMedCentralPubMedGoogle Scholar
  100. 100.
    Perrotta I, Russo E, Camastra C, Filice G, Di Mizio G, Colosimo F, Ricci P, Tripepi S, Amorosi A, Triumbari F, Donato G (2011) New evidence for a critical role of elastin in calcification of native heart valves: immunohistochemical and ultrastructural study with literature review. Histopathology 59:504–513PubMedGoogle Scholar
  101. 101.
    Flück M, Tunc-Civelek V, Chiquet M (2000) Rapid and reciprocal regulation of tenascin-C and tenascin-Y expression by loading of skeletal muscle. J Cell Sci 113:3583–3591PubMedGoogle Scholar
  102. 102.
    Chiquet M, Gelman L, Lutz R, Maier S (2009) From mechanostransduction to extracellular matrix gene expression in fibroblasts. Biochim Biophys Acta 1793:911–920PubMedGoogle Scholar
  103. 103.
    Hagios C, Koch M, Spring J, Chiquet M, Chiquet-Ehrismann R (1996) Tenascin-Y: a protein of novel domain structure is secreted by differentiated fibroblasts of muscle connective tissue. J Cell Biol 134:1499–1512PubMedGoogle Scholar
  104. 104.
    Berndt A, Kosmehl H, Katenkamp D, Tauchmann V (1994) Appearance of the myofibroblastic phenotype in Dupuytren’s disease is associated with a fibronectin, laminin, collagen type IV and tenascin extracellular matrix. Pathobiology 62:55–58PubMedGoogle Scholar
  105. 105.
    Mackey AL, Brandstetter S, Schjerling P, Bojsen-Moller J, Qvortrup K, Pedersen MM, Doessing S, Kjaer M, Magnusson SP, Langberg H (2011) Sequences response of extracellular matrix de-adhesion and fibrotic regulators after muscle damage is involved in protection against future injury in human skeletal muscle. FASEB J 25:1943–1959PubMedGoogle Scholar
  106. 106.
    Flück M, Mund SI, Schittny JC, Klossner S, Durieux AC, Giraud MN (2008) Mechano-regulated tenascin-C orchestrates muscle repair. Proc Natl Acad Sci U S A 105:13662–13667PubMedCentralPubMedGoogle Scholar
  107. 107.
    Murphy-Ullrich JE, Iozzo RV (2012) Thrombospondins in physiology and disease: new tricks for old dogs. Matrix Biol 31:152–154PubMedCentralPubMedGoogle Scholar
  108. 108.
    Adams JC, Lawler J (2004) The thrombospondins. Int J Biochem Cell Biol 36:961–968PubMedCentralPubMedGoogle Scholar
  109. 109.
    Adams JC, Lawler J (2011) The thrombospondins. Cold Spring Harb Perspect Biol 3:a00971Google Scholar
  110. 110.
    Mosher DF, Adams JC (2012) Adhesion-modulating/matricellular ECM protein families: a structural, functional and evolutionary appraisal. Matrix Biol 31:155–161PubMedGoogle Scholar
  111. 111.
    Lu A, Miao M, Schoeb TR, Agarwal A, Murphy-Ullrich JE (2011) Blockade of TSP-1 dependent TGF-beta activity reduces renal injury and proteinuria in a murine model of diabetic nephropathy. Am J Pathol 178:2573–2586PubMedGoogle Scholar
  112. 112.
    Belmadani S, Bernal J, Wei CC, Pallero MA, Dell’italia L, Murphy-Ullrich JE, Brecek KH (2007) A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II. Am J Pathol 171:777–789PubMedGoogle Scholar
  113. 113.
    Chipev CC, Simman R, Hatch G, Katz AE, Siegel DM, Simon M (2000) Myofibroblast phenotype and apoptosis in keloid and palmar fibroblasts in vitro. Cell Death Differ 7:166–176PubMedGoogle Scholar
  114. 114.
    Mimura Y, Ihn H, Jinnin M, Assano Y, Yamane K, Tamaki K (2005) Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts. Am J Pathol 166:1451–1463PubMedGoogle Scholar
  115. 115.
    Sweetwyne MT, Murphy-Ullrich JE (2012) Thrombospondin1 in tissue repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol 31:178–186PubMedCentralPubMedGoogle Scholar
  116. 116.
    Rogers NM, Yao M, Novelli EM, Thomson AW, Roberts DD, Isenberg JS (2012) Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management. Am J Physiol Renal Physiol 303:F1117–F1125PubMedGoogle Scholar
  117. 117.
    Agah A, Kyriakides TR, Lawler J, Bornstein P (2002) The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP/2-null mice. Am J Pathol 161:831–839PubMedGoogle Scholar
  118. 118.
    Hohenstein B, Daniel C, Hausknecht B, Boehmer K, Riess R, Amann KU, Hugo CP (2008) Correlation of enhanced thrombospondin-1 expression, TGF-beta signalling, and proteinuria in human type-2 diabetic nephropathy. Nephrol Dial Transplant 23:3880–3887PubMedGoogle Scholar
  119. 119.
    Chandrasekaran S, Guo NH, Rodrigues RG, Kaiser J, Roberts DD (1999) Pro-adhesive and chemotactic activities of thrombospondin-1 for breast carcinoma cells are mediated by alpha3beta1 integrin and regulated by insulin-like growth factor-1 and CD98. J Biol Chem 274:11408–11416PubMedGoogle Scholar
  120. 120.
    Chen H, Sottile J, Strickland DK, Mosher DF (1996) Binding and degradation of thrombospondin-1 mediated through heparan sulfate proteoglucans and low-density-lipoprotein receptor-related protein: localization of the functional activity to the trimeric N-terminal heparin-binding region of thrombospondin-1. Biochem J 318:959–963PubMedGoogle Scholar
  121. 121.
    Murphy-Ullrich JE, Poczatek M (2000) Activation of latent TGF-beta by thrombospondin-1: mechanism and physiology. Cytokine Growth Factor Rev 11:59–69PubMedGoogle Scholar
  122. 122.
    Elzie CA, Murphy-Ullrich JE (2004) The N-terminus of thrombospondin: the domain stands apart. Int J Biochem Cell Biol 36:1090–1101PubMedGoogle Scholar
  123. 123.
    Goldblum SE, Young BA, Wang P, Murphy-Ullrich JE (1999) Thrombospondin-1 induces tyrosine phosphorylation of adherens junction proteins and regulates an endothelial paracellular pathway. Mol Biol Cell 10:1537–1551PubMedCentralPubMedGoogle Scholar
  124. 124.
    Robert DD, Miller TW, Rogers NM, Yao M, Isenberg JS (2012) The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47. Matrix Biol 31:162–169Google Scholar
  125. 125.
    Hess D, Keusch JJ, Lesnik Oberstein SA, Hennekam RC, Hofsteenge J (2008) Peter plus syndrome is a new congenital disorder of glycosylation and involves defective O-glycosylation of thrombospondin type 1 repeats. J Biol Chem 283:7354–7360PubMedGoogle Scholar
  126. 126.
    Heinonen TY, Maki M (2009) Peters’-plus syndrome is a congenital disorder of glycosylation caused by a defect in the beta1,3-glucosyltransferase that modifies thrombospondin type 1 repeats. Ann Med 41:2–10PubMedGoogle Scholar
  127. 127.
    Shimizu R, Saito R, Hoshino K, Ogawa K, Negishi T, Nishimura J, Mitsui N, Osawa M, Ohashi H (2010) Severe Peters Plus syndrome-like phenotype with anterior eye staphyloma and hypoplastic left heart syndrome: proposal of a new syndrome. Congenit Anom (Kyoto) 50:197–199Google Scholar
  128. 128.
    Hanna NN, Eickholt K, Agamanolis D, Burnstine R, Edward DP (2010) Atypical Peters plus syndrome with new associations. J AAPOS 14:181–183PubMedGoogle Scholar
  129. 129.
    Eberwein P, Reinhard T, Agostini H, Poloschek CM, Guthoff R, Auw-Haedrich C (2010) Intensive intracorneal keloid formation in a case of Peters plus syndrome and in Peters anomaly with maximum manifestation. Ophthalmologe 107:178–181PubMedGoogle Scholar
  130. 130.
    Oldberg Å, Antonssen P, Lindholm K, Heinegård D (1992) COMP (cartilage oligomeric matrix protein) is structurally related to thrombospondins. J Biol Chem 267:22346–22350PubMedGoogle Scholar
  131. 131.
    Rock MJ, Holden P, Horton WA, Cohn DH (2010) Cartilage oligometric matrix protein promotes cell attachment via two independent mechanisms involving CD47 and αVβ3 integrin. Mol Cell Biochem 338:215–224PubMedCentralPubMedGoogle Scholar
  132. 132.
    Holden P, Meadows RS, Chapman KL, Grant ME, Kadler KE, Briggs MD (2001) Cartilage oligomeric matrix protein interacts with type IX collagen, and disruptions to these interactions identify a pathogenetic mechanism in a bone dysplasia family. J Biol Chem 276:6046–6055PubMedGoogle Scholar
  133. 133.
    Rosenberg K, Olsson H, Mörgelin M, Heinegård D (1998) Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen. J Biol Chem 273:20397–20403PubMedGoogle Scholar
  134. 134.
    Di Cesare P, Hauser N, Lehman D, Pasumarti S, Paulsson M (1994) Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon. FEBS Lett 354:237–240Google Scholar
  135. 135.
    Heinegård D (2009) Proteoglycans and more – from molecules to biology. Int J Exp Path 70:575–586Google Scholar
  136. 136.
    Smith RKW, Zunino L, Webbon PM, Heinegård D (1997) The distribution of cartilage oligomeric matrix protein (COMP) in tendon and its variation with tendon site, age and load. Matrix Biol 16:255–271PubMedGoogle Scholar
  137. 137.
    Södersten F, Hultenby K, Heinegård D, Johnston C, Ekman S (2013) Immunolocalization of collagens (I and III) and cartilage oligomeric matrix protein in the normal and injured equine superficial digital flexor tendon. Connect Tissue Res 54:62–69PubMedCentralPubMedGoogle Scholar
  138. 138.
    Halasz K, Kassner A, Morgelin M, Heinegård D (2007) COMP as a catalyst in collagen fibrillogenesis. J Biol Chem 282:31166–31173PubMedGoogle Scholar
  139. 139.
    Hesselstrand R, Kassner A, Heinegård D, Saxne T (2008) COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker. Ann Rheum Dis 67:1242–1248PubMedGoogle Scholar
  140. 140.
    Smith MR, Wright IM, Minshall GJ, Dudhia J, Verheyen K, Heinegård D, Smith RK (2011) Increased cartilage oligomeric matrix protein concentrations in equine digital flexor tendon sheath synovial fluid predicts interthecal tendon damage. Vet Surg 40:54–58PubMedGoogle Scholar
  141. 141.
    Wang L, Wang X, Kong W (2010) ADAMTS-7, a novel proteolytic culprit in vascular remodeling. Sheng Li Xue Bao 62:285–294PubMedGoogle Scholar
  142. 142.
    Riessen R, Fenchel M, Chen H, Axel DL, Karsch KR, Lawler J (2001) Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21:47–54PubMedGoogle Scholar
  143. 143.
    Riessen R, Isner JM, Blessing E, Loushin C, Nikol S, Wight TN (1994) Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries. Am J Pathol 144:962–974PubMedGoogle Scholar
  144. 144.
    Du Y, Wang Y, Wang L, Liu B, Tian Q, Liu CJ, Zhang T, Xu Q, Zhu Y, Ake O, Qi Y, Tang C, Kong W, Wang X (2011) Cartilage oligomeric matrix protein inhibits vascular smooth muscle calcification by interacting with bone morphogenetic protein-2. Circ Res 108:917–928PubMedGoogle Scholar
  145. 145.
    Posey KL, Hecht JT (2008) The role of cartilage oligomeric matrix protein (COMP) in skeletal disease. Curr Drug Targets 9:869–877PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of Pathology, College of Veterinary Medicine and Medical PartnershipThe University of GeorgiaAthensUSA
  2. 2.Institute of Sports MedicineBispebjerg HospitalCopenhagenDenmark
  3. 3.Centre of Healthy Aging, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations