Journal of Molecular Medicine

, Volume 92, Issue 9, pp 913–924

Molecular and cellular basis of scleroderma

  • Beate Eckes
  • Pia Moinzadeh
  • Gerhard Sengle
  • Nico Hunzelmann
  • Thomas Krieg


Systemic sclerosis (scleroderma) is a chronic inflammatory disease that leads to fibrosis of the skin and involved internal organs. No efficient therapy is currently available. This review summarizes recent progress made in basic as well as clinical science and concludes with a concept that therapy targeting fibrosis in scleroderma needs to take into account the global microenvironment in the skin with its diverse cellular players interacting with a complex extracellular matrix environment and matrix-associated growth factors.


Systemic sclerosis Scleroderma Extracellular microenvironment Pathophysiology Signaling 


  1. 1.
    Varga J (2012) Scleroderma—from pathogenesis to comprehensive management. Springer, New YorkGoogle Scholar
  2. 2.
    Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma. N Engl J Med 360:1989–2003PubMedGoogle Scholar
  3. 3.
    van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE et al (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 65:2737–2747PubMedGoogle Scholar
  4. 4.
    Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, Meurer M, Moinzadeh P, Muller-Ladner U, Pfeiffer C, Riemekasten G et al (2008) The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology (Oxford) 47:1185–1192Google Scholar
  5. 5.
    Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D (2003) Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 48:2246–2255PubMedGoogle Scholar
  6. 6.
    Allanore Y, Dieude P, Boileau C (2010) Genetic background of systemic sclerosis: autoimmune genes take centre stage. Rheumatology (Oxford) 49:203–210Google Scholar
  7. 7.
    Feghali-Bostwick C, Medsger TA Jr, Wright TM (2003) Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 48:1956–1963PubMedGoogle Scholar
  8. 8.
    Reveille JD (2003) Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations. Curr Rheumatol Rep 5:160–167PubMedGoogle Scholar
  9. 9.
    Arnett FC, Cho M, Chatterjee S, Aguilar MB, Reveille JD, Mayes MD (2001) Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum 44:1359–1362PubMedGoogle Scholar
  10. 10.
    Agarwal SK, Tan FK, Arnett FC (2008) Genetics and genomic studies in scleroderma (systemic sclerosis). Rheum Dis Clin North Am 34: 17-40; v. DOI 10.1016/j.rdc.2007.10.001
  11. 11.
    Zhou X, Tan FK, Wang N, Xiong M, Maghidman S, Reveille JD, Milewicz DM, Chakraborty R, Arnett FC (2003) Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Arthritis Rheum 48:2585–2592PubMedGoogle Scholar
  12. 12.
    Allanore Y, Saad M, Dieude P, Avouac J, Distler JH, Amouyel P, Matucci-Cerinic M, Riemekasten G, Airo P, Melchers I et al (2011) Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet 7:e1002091PubMedCentralPubMedGoogle Scholar
  13. 13.
    Dieude P, Guedj M, Wipff J, Avouac J, Fajardy I, Diot E, Granel B, Sibilia J, Cabane J, Mouthon L et al (2009) Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis. Arthritis Rheum 60:225–233PubMedGoogle Scholar
  14. 14.
    Rueda B, Gourh P, Broen J, Agarwal SK, Simeon C, Ortego-Centeno N, Vonk MC, Coenen M, Riemekasten G, Hunzelmann N et al (2010) BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians. Ann Rheum Dis 69:700–705PubMedCentralPubMedGoogle Scholar
  15. 15.
    Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R, Coenen MJ, Vonk MC, Voskuyl AE, Schuerwegh AJ et al (2010) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42:426–429PubMedCentralPubMedGoogle Scholar
  16. 16.
    Mayes MD, Bossini-Castillo L, Gorlova O, Martin JE, Zhou X, Chen WV, Assassi S, Ying J, Tan FK, Arnett FC et al (2014) Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am J Hum Genet 94:47–61PubMedCentralPubMedGoogle Scholar
  17. 17.
    Tan FK, Wang N, Kuwana M, Chakraborty R, Bona CA, Milewicz DM, Arnett FC (2001) Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum 44:893–901PubMedGoogle Scholar
  18. 18.
    Fonseca C, Lindahl GE, Ponticos M, Sestini P, Renzoni EA, Holmes AM, Spagnolo P, Pantelidis P, Leoni P, McHugh N et al (2007) A polymorphism in the CTGF promoter region associated with systemic sclerosis. N Engl J Med 357:1210–1220PubMedGoogle Scholar
  19. 19.
    Tan FK, Zhou X, Mayes MD, Gourh P, Guo X, Marcum C, Jin L, Arnett FC Jr (2006) Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford) 45:694–702Google Scholar
  20. 20.
    York MR, Nagai T, Mangini AJ, Lemaire R, van Seventer JM, Lafyatis R (2007) A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists. Arthritis Rheum 56:1010–1020PubMedGoogle Scholar
  21. 21.
    Christmann RB, Sampaio-Barros P, Stifano G, Borges CL, de Carvalho CR, Kairalla R, Parra ER, Spira A, Simms R, Capellozzi VL et al (2014) Association of Interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol 66:714–725PubMedGoogle Scholar
  22. 22.
    Galluccio F, Walker UA, Nihtyanova S, Moinzadeh P, Hunzelmann N, Krieg T, Steen V, Baron M, Sampaio-Barros P, Kayser C et al (2011) Registries in systemic sclerosis: a worldwide experience. Rheumatology (Oxford) 50:60–68Google Scholar
  23. 23.
    van Bon L, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L, Farina GA, Stifano G, Mathes AL, Cossu M et al (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433–443PubMedCentralPubMedGoogle Scholar
  24. 24.
    Nietert PJ, Silver RM (2000) Systemic sclerosis: environmental and occupational risk factors. Curr Opin Rheumatol 12:520–526PubMedGoogle Scholar
  25. 25.
    Namboodiri AM, Rocca KM, Pandey JP (2004) IgG antibodies to human cytomegalovirus late protein UL94 in patients with systemic sclerosis. Autoimmunity 37:241–244PubMedGoogle Scholar
  26. 26.
    Lunardi C, Dolcino M, Peterlana D, Bason C, Navone R, Tamassia N, Beri R, Corrocher R, Puccetti A (2006) Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach. PLoS Med 3:e2PubMedCentralPubMedGoogle Scholar
  27. 27.
    Nelson JL, Furst DE, Maloney S, Gooley T, Evans PC, Smith A, Bean MA, Ober C, Bianchi DW (1998) Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 351:559–562PubMedGoogle Scholar
  28. 28.
    Artlett CM, Smith JB, Jimenez SA (1998) Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med 338:1186–1191PubMedGoogle Scholar
  29. 29.
    Fleischmajer R, Perlish JS (1980) Capillary alterations in scleroderma. J Am Acad Dermatol 2:161–170PubMedGoogle Scholar
  30. 30.
    Matucci-Cerinic M, Kahaleh B, Wigley FM (2013) Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 65:1953–1962PubMedGoogle Scholar
  31. 31.
    Cutolo M, Sulli A, Pizzorni C, Accardo S (2000) Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol 27:155–160PubMedGoogle Scholar
  32. 32.
    Fleischmajer R, Perlish JS, West WP (1977) Ultrastructure of cutaneous cellular infiltrates in scleroderma. Arch Dermatol 113:1661–1666PubMedGoogle Scholar
  33. 33.
    Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, Adams LD, Furst DE, Schwartz SM (2008) Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One 3: e1452. DOI 10.1371/journal.pone.0001452
  34. 34.
    Kahaleh MB, Sherer GK, LeRoy EC (1979) Endothelial injury in scleroderma. J Exp Med 149:1326–1335PubMedGoogle Scholar
  35. 35.
    Riemekasten G, Philippe A, Nather M, Slowinski T, Muller DN, Heidecke H, Matucci-Cerinic M, Czirjak L, Lukitsch I, Becker M et al (2011) Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis 70:530–536PubMedGoogle Scholar
  36. 36.
    Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P (1992) Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 166:255–263PubMedGoogle Scholar
  37. 37.
    Antsiferova M, Martin C, Huber M, Feyerabend TB, Forster A, Hartmann K, Rodewald HR, Hohl D, Werner S (2013) Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis. J Immunol 191:6147–6155PubMedGoogle Scholar
  38. 38.
    Willenborg S, Eckes B, Brinckmann J, Krieg T, Waisman A, Hartmann K, Roers A, Eming SA (2014) Genetic ablation of mast cells redefines the role of mast cells in skin wound healing and bleomycin-induced fibrosis. J Invest Dermatol. doi:10.1038/jid.2014.12. 10.1038/jid.2014.12 PubMedGoogle Scholar
  39. 39.
    Wynn TA, Ramalingam TR (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18:1028–1040PubMedCentralPubMedGoogle Scholar
  40. 40.
    Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, McCalmont TH, Brown PO, Botstein D, Connolly MK (2003) Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A 100:12319–12324PubMedCentralPubMedGoogle Scholar
  41. 41.
    Whitfield ML (2014) Editorial: plasma and B cell gene signatures: quantitative targeting and monitoring of B cell-depleting therapies in autoimmune diseases in the genomic era. Arthritis Rheumatol 66:10–14PubMedGoogle Scholar
  42. 42.
    Yoshizaki A, Iwata Y, Komura K, Ogawa F, Hara T, Muroi E, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M et al (2008) CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol 172:1650–1663PubMedCentralPubMedGoogle Scholar
  43. 43.
    van Laar JM (2010) B-cell depletion with rituximab: a promising treatment for diffuse cutaneous systemic sclerosis. Arthritis Res Ther 12:112PubMedCentralPubMedGoogle Scholar
  44. 44.
    Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, Distler O (2014) Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204522 PubMedCentralGoogle Scholar
  45. 45.
    Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel PA, Simms RW (2009) B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 60:578–583PubMedCentralPubMedGoogle Scholar
  46. 46.
    Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, Karampetsou M, Yiannopoulos G, Andonopoulos AP (2010) Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 49:271–280Google Scholar
  47. 47.
    Bosello S, De Santis M, Lama G, Spano C, Angelucci C, Tolusso B, Sica G, Ferraccioli G (2010) B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res ther 12:R54PubMedCentralPubMedGoogle Scholar
  48. 48.
    Smith V, Piette Y, van Praet JT, Decuman S, Deschepper E, Elewaut D, De Keyser F (2013) Two-year results of an open pilot study of a 2-treatment course with rituximab in patients with early systemic sclerosis with diffuse skin involvement. J Rheumatol 40:52–57PubMedGoogle Scholar
  49. 49.
    Smith V, Van Praet JT, Vandooren B, Van der Cruyssen B, Naeyaert JM, Decuman S, Elewaut D, De Keyser F (2010) Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis 69:193–197PubMedGoogle Scholar
  50. 50.
    Abraham DJ, Krieg T, Distler J, Distler O (2009) Overview of pathogenesis of systemic sclerosis. Rheumatology (Oxford) 48(Suppl 3):iii3–7Google Scholar
  51. 51.
    Abraham D (2008) Connective tissue growth factor: growth factor, matricellular organizer, fibrotic biomarker or molecular target for anti-fibrotic therapy in SSc? Rheumatology (Oxford) 47(Suppl 5):v8–9Google Scholar
  52. 52.
    Doering K, Rosen A (2012) Autoantibodies in pathogenesis. In: Varga J, Denton CP, Wigley FM (eds) Scleroderma Springer, pp. 199-208Google Scholar
  53. 53.
    Mierau R, Moinzadeh P, Riemekasten G, Melchers I, Meurer M, Reichenberger F, Buslau M, Worm M, Blank N, Hein R et al (2011) Frequency of disease-associated and other nuclear autoantibodies in patients of the German Network for Systemic Scleroderma: correlation with characteristic clinical features. Arthritis Res Ther 13:R172PubMedCentralPubMedGoogle Scholar
  54. 54.
    Weiner ES, Earnshaw WC, Senecal JL, Bordwell B, Johnson P, Rothfield NF (1988) Clinical associations of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients. Arthritis Rheum 31:378–385PubMedGoogle Scholar
  55. 55.
    Steen VD, Powell DL, Medsger TA Jr (1988) Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 31:196–203PubMedGoogle Scholar
  56. 56.
    Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, Fraticelli P, Sambo P, Funaro A, Kazlauskas A et al (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667–2676PubMedGoogle Scholar
  57. 57.
    Renaudineau Y, Revelen R, Levy Y, Salojin K, Gilburg B, Shoenfeld Y, Youinou P (1999) Anti-endothelial cell antibodies in systemic sclerosis. Clin Diagn Lab Immunol 6:156–160PubMedCentralPubMedGoogle Scholar
  58. 58.
    Worda M, Sgonc R, Dietrich H, Niederegger H, Sundick RS, Gershwin ME, Wick G (2003) In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay. Arthritis Rheum 48:2605–2614PubMedGoogle Scholar
  59. 59.
    Mihai C, Tervaert JW (2010) Anti-endothelial cell antibodies in systemic sclerosis. Ann Rheum Dis 69:319–324PubMedGoogle Scholar
  60. 60.
    Chizzolini C, Raschi E, Rezzonico R, Testoni C, Mallone R, Gabrielli A, Facchini A, Del Papa N, Borghi MO, Dayer JM et al (2002) Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 46:1602–1613PubMedGoogle Scholar
  61. 61.
    Ronda N, Raschi E, Testoni C, Borghi MO, Gatti R, Dayer JM, Orlandini G, Chizzolini C, Meroni PL (2002) Anti-fibroblast antibodies in systemic sclerosis. Isr Med Assoc J 4:858–864PubMedGoogle Scholar
  62. 62.
    Tan FK, Arnett FC, Antohi S, Saito S, Mirarchi A, Spiera H, Sasaki T, Shoichi O, Takeuchi K, Pandey JP et al (1999) Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases. J Immunol 163:1066–1072PubMedGoogle Scholar
  63. 63.
    Sato S, Hayakawa I, Hasegawa M, Fujimoto M, Takehara K (2003) Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. J Invest Dermatol 120:542–547PubMedGoogle Scholar
  64. 64.
    Nishijima C, Hayakawa I, Matsushita T, Komura K, Hasegawa M, Takehara K, Sato S (2004) Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol 138:357–363PubMedCentralPubMedGoogle Scholar
  65. 65.
    Classen JF, Henrohn D, Rorsman F, Lennartsson J, Lauwerys BR, Wikstrom G, Rorsman C, Lenglez S, Franck-Larsson K, Tomasi JP et al (2009) Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum 60:1137–1144PubMedGoogle Scholar
  66. 66.
    Loizos N, Lariccia L, Weiner J, Griffith H, Boin F, Hummers L, Wigley F, Kussie P (2009) Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 60:1145–1151PubMedGoogle Scholar
  67. 67.
    Brinckmann J, Hunzelmann N, El-Hallous E, Krieg T, Sakai LY, Krengel S, Reinhardt DP (2005) Absence of autoantibodies against correctly folded recombinant fibrillin-1 protein in systemic sclerosis patients. Arthritis Res Ther 7:R1221–1226PubMedCentralPubMedGoogle Scholar
  68. 68.
    Ong VH, Denton CP (2012) Investigative approaches to drug therapy. In: Varga J, Denton CP, Wigley FM (eds) Scleroderma. Springer, New York, pp 603–614Google Scholar
  69. 69.
    Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L (2010) Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum 62:2787–2795PubMedCentralPubMedGoogle Scholar
  70. 70.
    Moinzadeh P, Fonseca C, Hellmich M, Shah AA, Chighizola C, Denton CP, Ong VH (2014) Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Res Ther 16:R53PubMedCentralPubMedGoogle Scholar
  71. 71.
    Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, Boin F, Fava A, Thoburn C, Kinde I et al (2014) Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343:152–157PubMedCentralPubMedGoogle Scholar
  72. 72.
    Teng MW, Smyth MJ (2014) Cancer. Can cancer trigger autoimmunity? Science 343:147–148PubMedGoogle Scholar
  73. 73.
    Fleischmajer R, Perlish JS, Shaw KV, Pirozzi DJ (1976) Skin capillary changes in early systemic scleroderma. Electron microscopy and "in vitro" autoradiography with tritiated thymidine. Arch Dermatol 112:1553–1557PubMedGoogle Scholar
  74. 74.
    Perlish JS, Lemlich G, Fleischmajer R (1988) Identification of collagen fibrils in scleroderma skin. J Invest Dermatol 90:48–54PubMedGoogle Scholar
  75. 75.
    LeRoy EC (1974) Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast. J Clin Invest 54:880–889PubMedCentralPubMedGoogle Scholar
  76. 76.
    Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573PubMedGoogle Scholar
  77. 77.
    Gerber EE, Gallo EM, Fontana SC, Davis EC, Wigley FM, Huso DL, Dietz HC (2013) Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503:126–130PubMedCentralPubMedGoogle Scholar
  78. 78.
    Agarwal P, Schulz JN, Blumbach K, Andreasson K, Heinegard D, Paulsson M, Mauch C, Eming SA, Eckes B, Krieg T (2013) Enhanced deposition of cartilage oligomeric matrix protein is a common feature in fibrotic skin pathologies. Matrix Biol J Int Soc Matrix Biol 32:325–331Google Scholar
  79. 79.
    Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326:1216–1219PubMedCentralPubMedGoogle Scholar
  80. 80.
    Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, De Wever O, Mareel M, Gabbiani G (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180:1340–1355PubMedCentralPubMedGoogle Scholar
  81. 81.
    Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117:557–567PubMedCentralPubMedGoogle Scholar
  82. 82.
    Hinz B (2010) The myofibroblast: paradigm for a mechanically active cell. J Biomech 43:146–155PubMedGoogle Scholar
  83. 83.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363PubMedGoogle Scholar
  84. 84.
    Herzog EL, Bucala R (2010) Fibrocytes in health and disease. Exp Hematol 38:548–556PubMedCentralPubMedGoogle Scholar
  85. 85.
    Strieter RM, Keeley EC, Hughes MA, Burdick MD, Mehrad B (2009) The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of pulmonary fibrosis. J Leukoc Biol 86:1111–1118PubMedCentralPubMedGoogle Scholar
  86. 86.
    Krieg T, Perlish JS, Fleischmajer R, Braun-Falco O (1985) Collagen synthesis in scleroderma: selection of fibroblast populations during subcultures. Arch Dermatol Res 277:373–376PubMedGoogle Scholar
  87. 87.
    Jelaska A, Strehlow D, Korn JH (1999) Fibroblast heterogeneity in physiological conditions and fibrotic disease. Springer Semin Immunopathol 21:385–395PubMedGoogle Scholar
  88. 88.
    Wang Y, Fan PS, Kahaleh B (2006) Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 54:2271–2279PubMedGoogle Scholar
  89. 89.
    Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, Muller CA, Kalluri R, Zeisberg M (2010) Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16:544–550PubMedCentralPubMedGoogle Scholar
  90. 90.
    Avouac J, Elhai M, Allanore Y (2013) Experimental models of dermal fibrosis and systemic sclerosis. Joint Bone Spine revue du rhumatisme 80:23–28Google Scholar
  91. 91.
    Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M (1998) Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J Invest Dermatol 110:47–51PubMedGoogle Scholar
  92. 92.
    Bhattacharyya S, Wei J, Varga J (2012) Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol 8:42–54Google Scholar
  93. 93.
    Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J et al (2012) Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun 3:735PubMedCentralPubMedGoogle Scholar
  94. 94.
    Beyer C, Distler JH (2013) Morphogen pathways in systemic sclerosis. Curr Rheumatol Rep 15:299PubMedGoogle Scholar
  95. 95.
    Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, Gottardi CJ, Atit R, Whitfield ML, Varga J (2012) Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum 64:2734–2745PubMedCentralPubMedGoogle Scholar
  96. 96.
    Konigshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L et al (2009) WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 119:772–787PubMedCentralPubMedGoogle Scholar
  97. 97.
    Fleischmajer R, Krieg T, Dziadek M, Altchek D, Timpl R (1984) Ultrastructure and composition of connective tissue in hyalinosis cutis et mucosae skin. J Invest Dermatol 82:252–258PubMedGoogle Scholar
  98. 98.
    Volloch V, Olsen BR (2013) Why cellular stress suppresses adipogenesis in skeletal tissue, but is ineffective in adipose tissue: control of mesenchymal cell differentiation via integrin binding sites in extracellular matrices. Matrix Biology J Int Soc Matrix Biol 32:365–371Google Scholar
  99. 99.
    Radovanac K, Morgner J, Schulz JN, Blumbach K, Patterson C, Geiger T, Mann M, Krieg T, Eckes B, Fassler R et al (2013) Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response. EMBO J 32:1409–1424PubMedCentralPubMedGoogle Scholar
  100. 100.
    Yamamoto T, Takagawa S, Katayama I, Yamazaki K, Hamazaki Y, Shinkai H, Nishioka K (1999) Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol 112:456–462PubMedGoogle Scholar
  101. 101.
    Hulmes DJ (2002) Building collagen molecules, fibrils, and suprafibrillar structures. J Struct Biol 137:2–10PubMedGoogle Scholar
  102. 102.
    Myllyharju J, Kivirikko KI (2004) Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 20:33–43PubMedGoogle Scholar
  103. 103.
    Hynes RO, Naba A (2012) Overview of the matrisome—an inventory of extracellular matrix constituents and functions. Cold Spring Harb Perspect Biol 4:a004903PubMedCentralPubMedGoogle Scholar
  104. 104.
    Eckes B, Nischt R, Krieg T (2010) Cell-matrix interactions in dermal repair and scarring. Fibrogenesis Tissue Repair 3:4PubMedCentralPubMedGoogle Scholar
  105. 105.
    Franzke CW, Bruckner P, Bruckner-Tuderman L (2005) Collagenous transmembrane proteins: recent insights into biology and pathology. J Biol Chem 280:4005–4008PubMedGoogle Scholar
  106. 106.
    Kadler KE, Baldock C, Bella J, Boot-Handford RP (2007) Collagens at a glance. J Cell Sci 120:1955–1958PubMedGoogle Scholar
  107. 107.
    Seth P, Yeowell HN (2010) Fox-2 protein regulates the alternative splicing of scleroderma-associated lysyl hydroxylase 2 messenger RNA. Arthritis Rheum 62:1167–1175PubMedCentralPubMedGoogle Scholar
  108. 108.
    Rimar D, Rosner I, Nov Y, Slobodin G, Rozenbaum M, Halasz K, Haj T, Jiries N, Kaly L, Boulman N et al (2013) Lysyl oxidase is a potential biomarker of fibrosis in systemic sclerosis. Arthritis Rheum. doi:10.1002/art.38277 Google Scholar
  109. 109.
    Brinckmann J, Kim S, Wu J, Reinhardt DP, Batmunkh C, Metzen E, Notbohm H, Bank RA, Krieg T, Hunzelmann N (2005) Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered cross-link pattern: important pathogenetic steps in early and late stage of systemic scleroderma? Matrix Biol J Int Soc Matrix Biol 24:459–468Google Scholar
  110. 110.
    Campbell ID, Humphries MJ (2011) Integrin structure, activation, and interactions. Cold Spring Harbor perspectives in biology 3. DOI 10.1101/cshperspect.a004994
  111. 111.
    Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233PubMedCentralPubMedGoogle Scholar
  112. 112.
    DuFort CC, Paszek MJ, Weaver VM (2011) Balancing forces: architectural control of mechanotransduction. Nat Rev Mol Cell Biol 12:308–319PubMedCentralPubMedGoogle Scholar
  113. 113.
    Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689PubMedGoogle Scholar
  114. 114.
    Erat MC, Slatter DA, Lowe ED, Millard CJ, Farndale RW, Campbell ID, Vakonakis I (2009) Identification and structural analysis of type I collagen sites in complex with fibronectin fragments. Proc Natl Acad Sci U S A 106:4195–4200PubMedCentralPubMedGoogle Scholar
  115. 115.
    Erat MC, Sladek B, Campbell ID, Vakonakis I (2013) Structural analysis of collagen type I interactions with human fibronectin reveals a cooperative binding mode. J Biol Chem 288:17441–17450PubMedCentralPubMedGoogle Scholar
  116. 116.
    Velling T, Risteli J, Wennerberg K, Mosher DF, Johansson S (2002) Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins alpha 11beta 1 and alpha 2beta 1. J Biol Chem 277:37377–37381PubMedGoogle Scholar
  117. 117.
    Kobayashi N, Kostka G, Garbe JH, Keene DR, Bachinger HP, Hanisch FG, Markova D, Tsuda T, Timpl R, Chu ML et al (2007) A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization. J Biol Chem 282:11805–11816PubMedGoogle Scholar
  118. 118.
    Finnis ML, Gibson MA (1997) Microfibril-associated glycoprotein-1 (MAGP-1) binds to the pepsin-resistant domain of the alpha3(VI) chain of type VI collagen. J Biol Chem 272:22817–22823PubMedGoogle Scholar
  119. 119.
    Siracusa LD, McGrath R, Ma Q, Moskow JJ, Manne J, Christner PJ, Buchberg AM, Jimenez SA (1996) A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res 6:300–313PubMedGoogle Scholar
  120. 120.
    Gayraud B, Keene DR, Sakai LY, Ramirez F (2000) New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse. J Cell Biol 150:667–680PubMedCentralPubMedGoogle Scholar
  121. 121.
    Loeys BL, Gerber EE, Riegert-Johnson D, Iqbal S, Whiteman P, McConnell V, Chillakuri CR, Macaya D, Coucke PJ, De Paepe A, Judge DP, Wigley F, Davis EC, Mardon HJ, Handford P, Keene DR, Sakai LY, Dietz HC (2010) Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med 2: 23ra20. DOI 10.1126/scitranslmed.3000488
  122. 122.
    Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, Zylberberg L, Collod-Beroud G, Bonnet D, Alanay Y et al (2011) Mutations in the TGFbeta binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet 89:7–14PubMedCentralPubMedGoogle Scholar
  123. 123.
    Sengle G, Tsutsui K, Keene DR, Tufa SF, Carlson EJ, Charbonneau NL, Ono RN, Sasaki T, Wirtz MK, Samples JR et al (2012) Microenvironmental regulation by fibrillin-1. PLoS Genet 8:e1002425PubMedCentralPubMedGoogle Scholar
  124. 124.
    Kessler D, Dethlefsen S, Haase I, Plomann M, Hirche F, Krieg T, Eckes B (2001) Fibroblasts in mechanically stressed collagen lattices assume a "synthetic" phenotype. J Biol Chem 276:36575–36585PubMedGoogle Scholar
  125. 125.
    Munger JS, Sheppard D (2011) Cross talk among TGF-beta signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb Perspect Biolo 3:a005017Google Scholar
  126. 126.
    Annes JP, Chen Y, Munger JS, Rifkin DB (2004) Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol 165:723–734PubMedCentralPubMedGoogle Scholar
  127. 127.
    Sheppard D (2005) Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev 24:395–402PubMedGoogle Scholar
  128. 128.
    Wipff PJ, Rifkin DB, Meister JJ, Hinz B (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 179:1311–1323PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Beate Eckes
    • 1
  • Pia Moinzadeh
    • 1
  • Gerhard Sengle
    • 2
    • 3
  • Nico Hunzelmann
    • 1
  • Thomas Krieg
    • 1
    • 3
    • 4
  1. 1.Department of DermatologyUniversity of CologneCologneGermany
  2. 2.Center for BiochemistryUniversity of CologneCologneGermany
  3. 3.Center for Molecular Medicine Cologne (CMMC)University of CologneCologneGermany
  4. 4.Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)University of CologneCologneGermany

Personalised recommendations