Scleroderma pp 267-282 | Cite as

Fibrosis: Insights from the Stiff Skin Syndrome

Chapter

Abstract

Fibrillin-1 is a 350-kDa glycoprotein component of the extracellular matrix. It is a member of a small family of homologous glycoproteins that includes the fibulins and the latent TGFβ-binding proteins (LTBPs). Fibrillin-1 has 43 calcium-binding epidermal growth factor-like (cbEGF-like) domains, 4 noncalcium-binding EGF-like domains, 7 TGFβ-binding protein-like (TB) domains, 2 hybrid domains, unique N and C-termini, and a 58-amino-acid proline-rich sequence. Fibrillin-1 is an integral constituent of complex structures in the extracellular matrix called microfibrils (Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol. 1986;103(3536967):2499–509). By electron microscopy (EM), microfibrils extracted from tissues or cell culture have a “bead-on-a-string” appearance, with periodically spaced globular domains connected by linear arms (McDowall M, Edwards NM, Jahoda CA, Hynd PI. The role of activins and follistatins in skin and hair follicle development and function. Cytokine Growth Factor Rev. 2008;19(5–6):415–26; Xu MY, Porte J, Knox AJ, et al. Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q). Am J Pathol. 2009;174(4):1264–79).

Keywords

Fibrillin Fibroblast Fibrosis Integrin Skin fibrosis insights Stiff skin syndrome TGF-beta 

References

  1. 1.
    Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol. 1986;103(3536967):2499–509.PubMedGoogle Scholar
  2. 2.
    McDowall M, Edwards NM, Jahoda CA, Hynd PI. The role of activins and follistatins in skin and hair follicle development and function. Cytokine Growth Factor Rev. 2008;19(5–6):415–26.PubMedGoogle Scholar
  3. 3.
    Xu MY, Porte J, Knox AJ, et al. Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q). Am J Pathol. 2009;174(4):1264–79.PubMedGoogle Scholar
  4. 4.
    Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci. 2002;115(Pt 14):2817–28.PubMedGoogle Scholar
  5. 5.
    Matt P, Schoenhoff F, Habashi J, et al. Circulating transforming growth factor-beta in Marfan syndrome. Circulation. 2009;120(6):526–32.PubMedGoogle Scholar
  6. 6.
    Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312(5770):117–21.PubMedGoogle Scholar
  7. 7.
    Ramirez F, Sakai LY, Dietz HC, Rifkin DB. Fibrillin microfibrils: multipurpose extracellular networks in organismal physiology. Physiol Genomics. 2004;19(15466717):151–4.PubMedGoogle Scholar
  8. 8.
    Ramirez F. Fibrillln mutations in Marfan syndrome and related phenotypes. Curr Opin Genet Dev. 1996;6(8791520):309–15.PubMedGoogle Scholar
  9. 9.
    Holm TM, Habashi JP, Doyle JJ, Bedja D, Chen Y, van Erp C, Lindsay M, Kim D, Schoenhoff F, Cohn RD, Loeys BL, Thomas C, Samarjit P, Marugan J, Judge DP, Dietz HC. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science. 2011;332(6027):358–61.PubMedGoogle Scholar
  10. 10.
    Loeys BL, Gerber EE, Riegert-Johnson D, et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med. 2010;2(23):23ra20.PubMedGoogle Scholar
  11. 11.
    Gayraud B, Keene DR, Sakai LY, Ramirez F. New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse. J Cell Biol. 2000;150(3):667–80.PubMedGoogle Scholar
  12. 12.
    Lemaire R, Farina G, Bayle J, et al. Antagonistic effect of the matricellular signaling protein CCN3 on TGF-beta- and Wnt-mediated fibrillinogenesis in systemic sclerosis and Marfan syndrome. J Invest Dermatol. 2010;130(6):1514–23.PubMedGoogle Scholar
  13. 13.
    Davis EC, Blattel SA, Mecham RP. Remodeling of elastic fiber components in scleroderma skin. Connect Tissue Res. 1999;40(2):113–21.PubMedGoogle Scholar
  14. 14.
    Tan FK, Stivers DN, Foster MW, et al. Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population. Arthritis Rheum. 1998;41(10):1729–37.PubMedGoogle Scholar
  15. 15.
    Tan FK, Wang N, Kuwana M, et al. Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum. 2001;44(4):893–901.PubMedGoogle Scholar
  16. 16.
    Zhou X, Tan FK, Wang N, et al. Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Arthritis Rheum. 2003;48(9):2585–92.PubMedGoogle Scholar
  17. 17.
    Arnett FC, Tan FK, Uziel Y, et al. Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin 1, in patients with localized scleroderma. Arthritis Rheum. 1999;42(12):2656–9.PubMedGoogle Scholar
  18. 18.
    Tan FK, Arnett FC, Reveille JD, et al. Autoantibodies to fibrillin 1 in systemic sclerosis: ethnic differences in antigen recognition and lack of correlation with specific clinical features or HLA alleles. Arthritis Rheum. 2000;43(11):2464–71.PubMedGoogle Scholar
  19. 19.
    Brinckmann J, Hunzelmann N, El-Hallous E, et al. Absence of autoantibodies against correctly folded recombinant fibrillin-1 protein in systemic sclerosis patients. Arthritis Res Ther. 2005;7(6):R1221–6.PubMedGoogle Scholar
  20. 20.
    Zhou X, Tan FK, Milewicz DM, Guo X, Bona CA, Arnett FC. Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the “scleroderma phenotype”. J Immunol. 2005;175(7):4555–60.PubMedGoogle Scholar
  21. 21.
    Wallis DD, Tan FK, Kessler R, et al. Fibrillin 1 abnormalities in dermal fibroblast cultures from first-degree relatives of patients with systemic sclerosis (scleroderma). Arthritis Rheum. 2004;50(1):329–32.PubMedGoogle Scholar
  22. 22.
    Wipff J, Avouac J, Le Charpentier M, et al. Dermal tissue and cellular expression of fibrillin-1 in diffuse cutaneous systemic sclerosis. Rheumatology. 2010;49(4):657–61.PubMedGoogle Scholar
  23. 23.
    Green MC, Sweet HO, Bunker LE. Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol. 1976;82(3):493–512.PubMedGoogle Scholar
  24. 24.
    Li X, Pereira L, Zhang H, et al. Fibrillin genes map to regions of conserved mouse/human synteny on mouse chromosomes 2 and 18. Genomics. 1993;18(3):667–72.PubMedGoogle Scholar
  25. 25.
    Siracusa LD, McGrath R, Ma Q, et al. A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res. 1996;6(4):300–13.PubMedGoogle Scholar
  26. 26.
    Bona CA, Murai C, Casares S, et al. Structure of the mutant fibrillin-1 gene in the tight skin (TSK) mouse. DNA Res. 1997;4(4):267–71.PubMedGoogle Scholar
  27. 27.
    Rossi GA, Hunninghake GW, Gadek JE, et al. Hereditary emphysema in the tight-skin mouse. Evaluation of pathogenesis. Am Rev Respir Dis. 1984;129(5):850–5.PubMedGoogle Scholar
  28. 28.
    Osborn TG, Bashey RI, Moore TL, Fischer VW. Collagenous abnormalities in the heart of the tight-skin mouse. J Mol Cell Cardiol. 1987;19(6):581–7.PubMedGoogle Scholar
  29. 29.
    Bona C, Rothfield N. Autoantibodies in scleroderma and tightskin mice. Curr Opin Immunol. 1994;6(6):931–7.PubMedGoogle Scholar
  30. 30.
    Osborn TG, Bauer NE, Ross SC, Moore TL, Zuckner J. The tight-skin mouse: physical and biochemical properties of the skin. J Rheumatol. 1983;10(5):793–6.PubMedGoogle Scholar
  31. 31.
    Jimenez SA, Williams CJ, Myers JC, Bashey RI. Increased collagen biosynthesis and increased expression of type I and type III procollagen genes in tight skin (TSK) mouse fibroblasts. J Biol Chem. 1986;261(2):657–62.PubMedGoogle Scholar
  32. 32.
    Esterly NB, McKusick VA. Stiff skin syndrome. Pediatrics. 1971;47(2):360–9.PubMedGoogle Scholar
  33. 33.
    Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352(1852208):337–9.PubMedGoogle Scholar
  34. 34.
    Isogai Z, Ono RN, Ushiro S, et al. Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem. 2003;278(12429738):2750–7.PubMedGoogle Scholar
  35. 35.
    Jones KB, Myers L, Judge DP, Kirby PA, Dietz HC, Sponseller PD. Toward an understanding of dural ectasia: a light microscopy study in a murine model of Marfan syndrome. Spine. 2005;30(15682009):291–3.PubMedGoogle Scholar
  36. 36.
    Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33(12598898):407–11.PubMedGoogle Scholar
  37. 37.
    Ng CM, Cheng A, Myers LA, et al. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004;114(15546004):1586–92.PubMedGoogle Scholar
  38. 38.
    Cohn RD, van Erp C, Habashi JP, et al. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med. 2007;13(17237794):204–10.PubMedGoogle Scholar
  39. 39.
    Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz 3rd HC. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med. 2008;358(26):2787–95.PubMedGoogle Scholar
  40. 40.
    Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275(47):36803–10.PubMedGoogle Scholar
  41. 41.
    Martin MM, Buckenberger JA, Jiang J, et al. TGF-beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways. Am J Physiol Lung Cell Mol Physiol. 2007;293(3):L790–9.PubMedGoogle Scholar
  42. 42.
    Peng F, Zhang B, Wu D, Ingram AJ, Gao B, Krepinsky JC. TGFbeta-induced RhoA activation and fibronectin production in mesangial cells require caveolae. Am J Physiol Renal Physiol. 2008;295(1):F153–64.PubMedGoogle Scholar
  43. 43.
    Wilkes MC, Mitchell H, Penheiter SG, et al. Transforming growth factor-beta activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res. 2005;65(22):10431–40.PubMedGoogle Scholar
  44. 44.
    Zuo W, Chen YG. Specific activation of mitogen-activated protein kinase by transforming growth factor-beta receptors in lipid rafts is required for epithelial cell plasticity. Mol Biol Cell. 2009;20(3):1020–9.PubMedGoogle Scholar
  45. 45.
    Habashi JP, Doyle JJ, Holm TM, Aziz H, Scoenhoff F, Bedja D, Chen Y, Modiri AN, Judge DP, Dietz HC. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science. 2011;332(6027):361–5.PubMedGoogle Scholar
  46. 46.
    Kielty CM, Raghunath M, Siracusa LD, et al. The tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils. J Cell Biol. 1998;140(5):1159–66.PubMedGoogle Scholar
  47. 47.
    Chatterjee S, Mark ME, Wooley PH, Lawrence WD, Mayes MD. Increased dermal elastic fibers in the tight skin mouse. Clin Exp Rheumatol. 2004;22(5):617–20.PubMedGoogle Scholar
  48. 48.
    Lemaire R, Korn JH, Schiemann WP, Lafyatis R. Fibulin-2 and fibulin-5 alterations in tsk mice associated with disorganized hypodermal elastic fibers and skin tethering. J Invest Dermatol. 2004;123(15610515):1063–9.PubMedGoogle Scholar
  49. 49.
    Saito S, Nishimura H, Phelps RG, et al. Induction of skin fibrosis in mice expressing a mutated fibrillin-1 gene. Mol Med. 2000;6(10):825–36.PubMedGoogle Scholar
  50. 50.
    Menon RP, Menon MR, Shi-Wen X, et al. Hammerhead ribozyme-mediated silencing of the mutant fibrillin-1 of tight skin mouse: insight into the functional role of mutant fibrillin-1. Exp Cell Res. 2006;312(9):1463–74.PubMedGoogle Scholar
  51. 51.
    Hanssen E, Hew FH, Moore E, Gibson MA. MAGP-2 has multiple binding regions on fibrillins and has covalent periodic association with fibrillin-containing microfibrils. J Biol Chem. 2004;279(28):29185–94.PubMedGoogle Scholar
  52. 52.
    Penner AS, Rock MJ, Kielty CM, Shipley JM. Microfibril-associated glycoprotein-2 interacts with fibrillin-1 and fibrillin-2 suggesting a role for MAGP-2 in elastic fiber assembly. J Biol Chem. 2002;277(38):35044–9.PubMedGoogle Scholar
  53. 53.
    Gibson MA, Hatzinikolas G, Kumaratilake JS, et al. Further characterization of proteins associated with elastic fiber microfibrils including the molecular cloning of MAGP-2 (MP25). J Biol Chem. 1996;271(8557636):1096–103.PubMedGoogle Scholar
  54. 54.
    Gibson MA, Leavesley DI, Ashman LK. Microfibril-associated glycoprotein-2 specifically interacts with a range of bovine and human cell types via alphaVbeta3 integrin. J Biol Chem. 1999;274(10224057):13060–5.PubMedGoogle Scholar
  55. 55.
    Lemaire R, Farina G, Kissin E, et al. Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen. Arthritis Rheum. 2004;50(15022335):915–26.PubMedGoogle Scholar
  56. 56.
    Lemaire R, Korn JH, Shipley JM, Lafyatis R. Increased expression of type I collagen induced by microfibril-associated glycoprotein 2: novel mechanistic insights into the molecular basis of dermal fibrosis in scleroderma. Arthritis Rheum. 2005;52(15934076):1812–23.PubMedGoogle Scholar
  57. 57.
    Dooley A, Low SY, Holmes A, et al. Nitric oxide synthase expression and activity in the tight-skin mouse model of fibrosis. Rheumatology. 2008;47(18238792):272–80.PubMedGoogle Scholar
  58. 58.
    Andersen GN, Caidahl K, Kazzam E, et al. Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Arthritis Rheum. 2000;43(10817563):1085–93.PubMedGoogle Scholar
  59. 59.
    Cotton SA, Herrick AL, Jayson MI, Freemont AJ. Endothelial expression of nitric oxide synthases and nitrotyrosine in systemic sclerosis skin. J Pathol. 1999;189(10547586):273–8.PubMedGoogle Scholar
  60. 60.
    Yamamoto T, Katayama I, Nishioka K. Nitric oxide production and inducible nitric oxide synthase expression in systemic sclerosis. J Rheumatol. 1998;25(9489825):314–7.PubMedGoogle Scholar
  61. 61.
    Dooley A, Gao B, Bradley N, et al. Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine. Rheumatology. 2006;45(16399843):676–84.PubMedGoogle Scholar
  62. 62.
    Sambo P, Baroni SS, Luchetti M, et al. Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum. 2001;44(11710721):2653–64.PubMedGoogle Scholar
  63. 63.
    Herrick AL, Illingworth KJ, Hollis S, Gomez-Zumaquero JM, Tinahones FJ. Antibodies against oxidized low-density lipoproteins in systemic sclerosis. Rheumatology. 2001;40(11312377):401–5.PubMedGoogle Scholar
  64. 64.
    Tikly M, Channa K, Theodorou P, Gulumian M. Lipid peroxidation and trace elements in systemic sclerosis. Clin Rheumatol. 2006;25(16249831):320–4.PubMedGoogle Scholar
  65. 65.
    Cracowski J-L, Carpentier PH, Imbert B, et al. Increased urinary F2-isoprostanes in systemic sclerosis, but not in primary Raynaud’s phenomenon: effect of cold exposure. Arthritis Rheum. 2002;46(12115239):1319–23.PubMedGoogle Scholar
  66. 66.
    Ogawa F, Shimizu K, Muroi E, et al. Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis. Rheumatology. 2006;45(7):815–8.PubMedGoogle Scholar
  67. 67.
    Bruckdorfer KR, Hillary JB, Bunce T, Vancheeswaran R, Black CM. Increased susceptibility to oxidation of low-density lipoproteins isolated from patients with systemic sclerosis. Arthritis Rheum. 1995;38(8):1060–7.PubMedGoogle Scholar
  68. 68.
    Herrick AL, Matucci Cerinic M. The emerging problem of oxidative stress and the role of antioxidants in systemic sclerosis. Clin Exp Rheumatol. 2001;19(1):4–8.PubMedGoogle Scholar
  69. 69.
    Simonini G, Pignone A, Generini S, et al. Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. Toxicology. 2000;155(11154792):1–15.PubMedGoogle Scholar
  70. 70.
    Chung MP, Monick MM, Hamzeh NY, Butler NS, Powers LS, Hunninghake GW. Role of repeated lung injury and genetic background in bleomycin-induced fibrosis. Am J Respir Cell Mol Biol. 2003;29(12676806):375–80.PubMedGoogle Scholar
  71. 71.
    Yoshimura S, Nishimura Y, Nishiuma T, Yamashita T, Kobayashi K, Yokoyama M. Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balance. Respirology. 2006;11(16916326):546–56.PubMedGoogle Scholar
  72. 72.
    Hasegawa M, Fujimoto M, Takehara K, Sato S. Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis. J Dermatol Sci. 2005;39(1):1–7.PubMedGoogle Scholar
  73. 73.
    Walker MA, Harley RA, DeLustro FA, LeRoy EC. Adoptive transfer of tsk skin fibrosis to +/+ recipients by tsk bone marrow and spleen cells. Proc Soc Exp Biol Med. 1989;192(2):196–200.PubMedGoogle Scholar
  74. 74.
    Dodig TD, Mack KT, Cassarino DF, Clark SH. Development of the tight-skin phenotype in immune-deficient mice. Arthritis Rheum. 2001;44(11263788):723–7.PubMedGoogle Scholar
  75. 75.
    Pablos JL, Everett ET, Norris JS. The tight skin mouse: an animal model of systemic sclerosis. Clin Exp Rheumatol. 2004;22(15344604):81–5.Google Scholar
  76. 76.
    Siracusa LD, McGrath R, Fisher JK, Jimenez SA. The mouse tight skin (Tsk) phenotype is not dependent on the presence of mature T and B lymphocytes. Mamm Genome. 1998;9(11):907–9.PubMedGoogle Scholar
  77. 77.
    Murai C, Saito S, Kasturi KN, Bona CA. Spontaneous occurrence of anti-fibrillin-1 autoantibodies in tight-skin mice. Autoimmunity. 1998;28(9867127):151–5.PubMedGoogle Scholar
  78. 78.
    Steen VD, Powell DL, Medsger Jr TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 1988;31(2):196–203.PubMedGoogle Scholar
  79. 79.
    Kuwana M, Kaburaki J, Mimori T, Tojo T, Homma M. Autoantibody reactive with three classes of RNA polymerases in sera from patients with systemic sclerosis. J Clin Invest. 1993;91(4):1399–404.PubMedGoogle Scholar
  80. 80.
    Saito E, Fujimoto M, Hasegawa M, et al. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest. 2002;109(11):1453–62.PubMedGoogle Scholar
  81. 81.
    Asano N, Fujimoto M, Yazawa N, et al. B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse. Am J Pathol. 2004;165(2):641–50.PubMedGoogle Scholar
  82. 82.
    Batten M, Groom J, Cachero TG, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med. 2000;192(11085747):1453–66.PubMedGoogle Scholar
  83. 83.
    Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190(11):1697–710.PubMedGoogle Scholar
  84. 84.
    Khare SD, Sarosi I, Xia XZ, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA. 2000;97(7):3370–5.PubMedGoogle Scholar
  85. 85.
    Matsushita T, Fujimoto M, Hasegawa M, et al. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J Invest Dermatol. 2007;127(12):2772–80.PubMedGoogle Scholar
  86. 86.
    Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94.PubMedGoogle Scholar
  87. 87.
    Komura K, Fujimoto M, Yanaba K, et al. Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse. Ann Rheum Dis. 2008;67(17823201):867–72.PubMedGoogle Scholar
  88. 88.
    Wallace VA, Kondo S, Kono T, et al. A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice. Eur J Immunol. 1994;24(6):1463–6.PubMedGoogle Scholar
  89. 89.
    Needleman BW, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthritis Rheum. 1992;35(1):67–72.PubMedGoogle Scholar
  90. 90.
    Ihn H, Sato S, Fujimoto M, Kikuchi K, Takehara K. Demonstration of interleukin-2, interleukin-4 and interleukin-6 in sera from patients with localized scleroderma. Arch Dermatol Res. 1995;287(2):193–7.PubMedGoogle Scholar
  91. 91.
    Ong CJ, Ip S, Teh SJ, et al. A role for T helper 2 cells in mediating skin fibrosis in tight-skin mice. Cell Immunol. 1999;196(1):60–8.PubMedGoogle Scholar
  92. 92.
    Ong C, Wong C, Roberts CR, Teh HS, Jirik FR. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol. 1998;28(9):2619–29.PubMedGoogle Scholar
  93. 93.
    Kodera T, McGaha TL, Phelps R, Paul WE, Bona CA. Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-beta production by fibroblasts. Proc Natl Acad Sci USA. 2002;99(11891315):3800–5.PubMedGoogle Scholar
  94. 94.
    Peterkofsky B, Diegelmann R. Use of a mixture of proteinase-free collagenases for the specific assay of radioactive collagen in the presence of other proteins. Biochemistry. 1971;10(6):988–94.PubMedGoogle Scholar
  95. 95.
    Hatakeyama A, Kasturi KN, Wolf I, Phelps RG, Bona CA. Correlation between the concentration of serum anti-topoisomerase I autoantibodies and histological and biochemical alterations in the skin of tight skin mice. Cell Immunol. 1996;167(1):135–40.PubMedGoogle Scholar
  96. 96.
    Tsuji-Yamada J, Nakazawa M, Takahashi K, et al. Effect of IL-12 encoding plasmid administration on tight-skin mouse. Biochem Biophys Res Commun. 2001;280(3):707–12.PubMedGoogle Scholar
  97. 97.
    Ong VH, Evans LA, Shiwen X, et al. Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse. Arthritis Rheum. 2003;48(7):1979–91.PubMedGoogle Scholar
  98. 98.
    Hasegawa M, Matsushita Y, Horikawa M, et al. A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis. Arthritis Rheum. 2009;60(11):3465–75.PubMedGoogle Scholar
  99. 99.
    Akhmetshina A, Venalis P, Dees C, et al. Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum. 2009;60(1):219–24.PubMedGoogle Scholar
  100. 100.
    Yoshizaki A, Yanaba K, Iwata Y, et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 2010;62(8):2476–87.PubMedGoogle Scholar
  101. 101.
    Fried L, Kirsner RS, Bhandarkar S, Arbiser JL. Efficacy of rapamycin in scleroderma: a case study. Lymphat Res Biol. 2008;6(3–4):217–9.PubMedGoogle Scholar
  102. 102.
    Su TI, Khanna D, Furst DE, et al. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum. 2009;60(12):3821–30.PubMedGoogle Scholar
  103. 103.
    Bayle J, Fitch J, Jacobsen K, Kumar R, Lafyatis R, Lemaire R. Increased expression of Wnt2 and SFRP4 in Tsk mouse skin: role of Wnt signaling in altered dermal fibrillin deposition and systemic sclerosis. J Invest Dermatol. 2008;128(4):871–81.PubMedGoogle Scholar
  104. 104.
    Chen S, McLean S, Carter DE, Leask A. The gene expression profile induced by Wnt 3a in NIH 3T3 fibroblasts. J Cell Commun Signal. 2007;1(3–4):175–83.PubMedGoogle Scholar
  105. 105.
    Amoric JC, Stalder JF, David A, Bureau B, Pierard GE, Litoux P. Dysmorphism in stiff skin syndrome. Ann Dermatol Venereol. 1991;118(11):802–4.PubMedGoogle Scholar
  106. 106.
    Bodemer C, Habib K, Teillac D, Munich A, de Prost Y. A new case of stiff skin syndrome. Ann Dermatol Venereol. 1991;118(11):805–6.PubMedGoogle Scholar
  107. 107.
    Bundy SE, Lie K. Stiff skin syndrome. Birth Defects Orig Artic Ser. 1975;11(2):360–1.PubMedGoogle Scholar
  108. 108.
    DiRocco M. Clinical images: stiff skin syndrome. Arthritis Rheum. 2000;43(7):1542.PubMedGoogle Scholar
  109. 109.
    Esterly NB. The stiff skin syndrome. Birth Defects Orig Artic Ser. 1971;7(8):306–8.PubMedGoogle Scholar
  110. 110.
    Ferrari D, Rossi R, Donzelli O. Stiff-skin syndrome. Chir Organi Mov. 2005;90(1):69–73.PubMedGoogle Scholar
  111. 111.
    Gilaberte Y, Saenz-de-Santamaria MC, Garcia-Latasa FJ, Gonzalez-Mediero I, Zambrano A. Stiff skin syndrome: a case report and review of the literature. Dermatology. 1995;190(2):148–51.PubMedGoogle Scholar
  112. 112.
    Helm TN, Wirth PB, Helm KF. Congenital fascial dystrophy: the stiff skin syndrome. Cutis. 1997;60(3):153–4.PubMedGoogle Scholar
  113. 113.
    Jablonska S, Blaszczyk M. Scleroderma-like indurations involving fascias: an abortive form of congenital fascial dystrophy (stiff skin syndrome). Pediatr Dermatol. 2000;17(2):105–10.PubMedGoogle Scholar
  114. 114.
    Jablonska S, Blaszczyk M. Stiff skin syndrome is highly heterogeneous, and congenital fascial dystrophy is its distinct subset. Pediatr Dermatol. 2004;21(4):508–10.PubMedGoogle Scholar
  115. 115.
    Jablonska S, Groniowski J, Krieg T, et al. Congenital fascial dystrophy–a noninflammatory disease of fascia: the stiff skin syndrome. Pediatr Dermatol. 1984;2(2):87–97.PubMedGoogle Scholar
  116. 116.
    Jablonska S, Schubert H, Kikuchi I. Congenital fascial dystrophy: stiff skin syndrome–a human counterpart of the tight-skin mouse. J Am Acad Dermatol. 1989;21(5 Pt 1):943–50.PubMedGoogle Scholar
  117. 117.
    Le T, Pierard GE. Stiff skin syndrome. Ann Dermatol Venereol. 1989;116(11):807–9.PubMedGoogle Scholar
  118. 118.
    Liu T, McCalmont TH, Frieden IJ, Williams ML, Connolly MK, Gilliam AE. The stiff skin syndrome: case series, differential diagnosis of the stiff skin phenotype, and review of the literature. Arch Dermatol. 2008;144(10):1351–9.PubMedGoogle Scholar
  119. 119.
    Qin Y, Yan J, Simpson JL, Gu HF, Wang LC, Chen ZJ. Novel non-synonymous mutation in the transforming growth factor beta binding protein-like (TB) domain of the fibrillin-1 (FBN1) gene in a Han Chinese family with Marfan syndrome (MFS). Neuro Endocrinol Lett. 2007;28(5):629–32.PubMedGoogle Scholar
  120. 120.
    Sakamoto H, Broekelmann T, Cheresh DA, Ramirez F, Rosenbloom J, Mecham RP. Cell-type specific recognition of RGD- and non-RGD-containing cell binding domains in fibrillin-1. J Biol Chem. 1996;271(9):4916–22.PubMedGoogle Scholar
  121. 121.
    Pfaff M, Reinhardt DP, Sakai LY, Timpl R. Cell adhesion and integrin binding to recombinant human fibrillin-1. FEBS Lett. 1996;384(3):247–50.PubMedGoogle Scholar
  122. 122.
    Arteaga-Solis E, Gayraud B, Lee SY, Shum L, Sakai L, Ramirez F. Regulation of limb patterning by extracellular microfibrils. J Cell Biol. 2001;154(2):275–81.PubMedGoogle Scholar
  123. 123.
    Takahashi S, Leiss M, Moser M, et al. The RGD motif in fibronectin is essential for development but dispensable for fibril assembly. J Cell Biol. 2007;178(1):167–78.PubMedGoogle Scholar
  124. 124.
    Jovanovic J, Iqbal S, Jensen S, Mardon H, Handford P. Fibrillin-integrin interactions in health and disease. Biochem Soc Trans. 2008;36(Pt 2):257–62.PubMedGoogle Scholar
  125. 125.
    Jovanovic J, Takagi J, Choulier L, et al. alphaVbeta6 is a novel receptor for human fibrillin-1. Comparative studies of molecular determinants underlying integrin-RGD affinity and specificity. J Biol Chem. 2007;282(9):6743–51.PubMedGoogle Scholar
  126. 126.
    Bax DV, Bernard SE, Lomas A, et al. Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by alpha 5 beta 1 and alpha v beta 3 integrins. J Biol Chem. 2003;278(36):34605–16.PubMedGoogle Scholar
  127. 127.
    D’Arrigo C, Burl S, Withers AP, Dobson H, Black C, Boxer M. TGF-beta1 binding protein-like modules of fibrillin-1 and -2 mediate integrin-dependent cell adhesion. Connect Tissue Res. 1998;37(1–2):29–51.PubMedGoogle Scholar
  128. 128.
    Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep. 2009;11(2):120–6.PubMedGoogle Scholar
  129. 129.
    Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–76.PubMedGoogle Scholar
  130. 130.
    Galliher AJ, Schiemann WP. Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res. 2006;8(4):R42.PubMedGoogle Scholar
  131. 131.
    Scaffidi AK, Petrovic N, Moodley YP, et al. alpha(v)beta(3) Integrin interacts with the transforming growth factor beta (TGFbeta) type II receptor to potentiate the proliferative effects of TGFbeta1 in living human lung fibroblasts. J Biol Chem. 2004;279(36):37726–33.PubMedGoogle Scholar
  132. 132.
    Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1 – an intimate relationship. Eur J Cell Biol. 2008;87(8–9):601–15.PubMedGoogle Scholar
  133. 133.
    Yang Z, Mu Z, Dabovic B, et al. Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice. J Cell Biol. 2007;176(6):787–93.PubMedGoogle Scholar
  134. 134.
    Asano Y, Ihn H, Jinnin M, Mimura Y, Tamaki K. Involvement of alphavbeta5 integrin in the establishment of autocrine TGF-beta signaling in dermal fibroblasts derived from localized scleroderma. J Invest Dermatol. 2006;126(8):1761–9.PubMedGoogle Scholar
  135. 135.
    Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J Immunol. 2005;175(11):7708–18.PubMedGoogle Scholar
  136. 136.
    Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum. 2005;52(9):2897–905.PubMedGoogle Scholar
  137. 137.
    Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K. Increased expression levels of integrin alphavbeta5 on scleroderma fibroblasts. Am J Pathol. 2004;164(4):1275–92.PubMedGoogle Scholar
  138. 138.
    Gardner HA. Integrin signaling in fibrosis and scleroderma. Curr Rheumatol Rep. 1999;1(1):28–33.PubMedGoogle Scholar
  139. 139.
    Hong W, Chen M, Kong X, Liao W. Effect of integrin on procollagen synthesis by fibroblasts from scleroderma. Chin Med J. 1999;112(11):1024–7.PubMedGoogle Scholar
  140. 140.
    Iannone F, Matucci-Cerinic M, Falappone PC, et al. Distinct expression of adhesion molecules on skin fibroblasts from patients with diffuse and limited systemic sclerosis. A pilot study. J Rheumatol. 2005;32(10):1893–8.PubMedGoogle Scholar
  141. 141.
    Liu S, Kapoor M, Denton CP, Abraham DJ, Leask A. Loss of beta1 integrin in mouse fibroblasts results in resistance to skin scleroderma in a mouse model. Arthritis Rheum. 2009;60(9):2817–21.PubMedGoogle Scholar
  142. 142.
    Goodwin A, Jenkins G. Role of integrin-mediated TGFbeta activation in the pathogenesis of pulmonary fibrosis. Biochem Soc Trans. 2009;37(Pt 4):849–54.PubMedGoogle Scholar
  143. 143.
    Horan GS, Wood S, Ona V, et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med. 2008;177(1):56–65.PubMedGoogle Scholar
  144. 144.
    Munger JS, Huang X, Kawakatsu H, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96(3):319–28.PubMedGoogle Scholar
  145. 145.
    Nishimura SL. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol. 2009;175(4):1362–70.PubMedGoogle Scholar
  146. 146.
    Sheppard D. Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis. Chest. 2001;120(1 Suppl):49S–53.PubMedGoogle Scholar
  147. 147.
    Sheppard D. Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev. 2005;24(3):395–402.PubMedGoogle Scholar
  148. 148.
    Blystone SD, Slater SE, Williams MP, Crow MT, Brown EJ. A molecular mechanism of integrin crosstalk: alphavbeta3 suppression of calcium/calmodulin-dependent protein kinase II regulates alpha5beta1 function. J Cell Biol. 1999;145(4):889–97.PubMedGoogle Scholar
  149. 149.
    Calderwood DA, Tai V, Di Paolo G, De Camilli P, Ginsberg MH. Competition for talin results in trans-dominant inhibition of integrin activation. J Biol Chem. 2004;279(28):28889–95.PubMedGoogle Scholar
  150. 150.
    Diaz-Gonzalez F, Forsyth J, Steiner B, Ginsberg MH. Trans-dominant inhibition of integrin function. Mol Biol Cell. 1996;7(12):1939–51.PubMedGoogle Scholar
  151. 151.
    Gonzalez AM, Bhattacharya R, deHart GW, Jones JC. Transdominant regulation of integrin function: mechanisms of crosstalk. Cell Signal. 2010;22(4):578–83.PubMedGoogle Scholar
  152. 152.
    Schwartz MA, Ginsberg MH. Networks and crosstalk: integrin signalling spreads. Nat Cell Biol. 2002;4(4):E65–8.PubMedGoogle Scholar
  153. 153.
    Hayashida T, Jones JC, Lee CK, Schnaper HW. Loss of beta1-integrin enhances TGF-beta1-induced collagen expression in epithelial cells via increased alphavbeta3-integrin and Rac1 activity. J Biol Chem. 2010;285(40):30741–51.PubMedGoogle Scholar
  154. 154.
    Patsenker E, Popov Y, Stickel F, et al. Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology. 2009;50(5):1501–11.PubMedGoogle Scholar
  155. 155.
    Alghisi GC, Ponsonnet L, Ruegg C. The integrin antagonist cilengitide activates alphaVbeta3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells. PLoS One. 2009;4(2):e4449.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Departments of Pediatrics, Medicine and Molecular Biology and Genetics and Institute of Genetic MedicineJohns Hopkins University School of Medicine and Howard Hughes Medical InstituteBaltimoreUSA

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