Archives of Dermatological Research

, Volume 302, Issue 5, pp 319–339

Genetics of keloid scarring

Mini Review

Abstract

Keloid scarring, also known as keloid disease (KD), is a common, abnormally raised fibroproliferative cutaneous lesion that can occur following even minor skin trauma. The aetiopathogenesis of KD has remained an enigma todate compounded by an ill-defined clinical management. There is strong evidence suggesting a genetic susceptibility in individuals affected by KD, including familial heritability, common occurrence in twins and high prevalence in certain ethnic populations. This review aims to address the genetic aspects of KD that have been described in present literature that include inheritance patterns, linkage studies, case–control association studies, whole genome gene expression microarray studies and gene pathways that were significant in KD. In addition to our clinical and scientific background in KD, we used search engines, Scopus, Scirus and PubMed, which searched for key terms covering various genetic aspects of KD. Additionally, genes reported in seven whole genome gene expression microarray studies were separately compared in detail. Our findings indicate a varied inheritance pattern in KD (predominantly autosomal dominant), linkage loci (chromosomes 2q23 and 7p11), several human leukocyte antigen (HLA) alleles (HLA-DRB1*15, HLA-DQA1*0104, DQ-B1*0501 and DQB1*0503), negative candidate gene case–control association studies and at least 25 dysregulated genes reported in multiple microarray studies. The major pathways reportedly proposed to be involved in KD include apoptosis, mitogen-activated protein kinase, transforming growth factor-β, interleukin-6 and plasminogen activator inhibitor-1. In summary, involvement of more than one gene is likely to be responsible for susceptibility to KD. A better understanding of the genes involved in KD may potentially lead to the development of more effective diagnostic, therapeutic and prognostic measures.

Keywords

Keloid scarring Keloid disease Cutaneous fibrosis Genetics Susceptibility Predisposition Inheritance Linkage Gene expression Genotype–phenotype association 

References

  1. 1.
    Abderrahmani R, Francois A, Buard V, Benderitter M, Sabourin JC, Crandall DL, Milliat F (2009) Effects of pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 in radiation-induced intestinal injury. Int J Radiat Oncol Biol Phys 74(3):942–948PubMedGoogle Scholar
  2. 2.
    Akaishi S, Ogawa R, Hyakusoku H (2008) Keloid and hypertrophic scar: neurogenic inflammation hypotheses. Med Hypotheses 71(1):32–38PubMedGoogle Scholar
  3. 3.
    Alaish SM, Yager DR, Diegelmann RF, Cohen IK (1995) Hyaluronic acid metabolism in keloid fibroblasts. J Pediatr Surg 30(7):949–952PubMedGoogle Scholar
  4. 4.
    Alonso PE, Rioja LF, Pera C (2008) Keloids: a viral hypothesis. Med Hypotheses 70(1):156–166PubMedGoogle Scholar
  5. 5.
    Amadeu TP, Braune AS, Porto LC, Desmouliere A, Costa AM (2004) Fibrillin-1 and elastin are differentially expressed in hypertrophic scars and keloids. Wound Repair Regen 12(2):169–174PubMedGoogle Scholar
  6. 6.
    Bayat A, Arscott G, Ollier WE, Ferguson MW, McGrouther DA (2003) “Aggressive keloid”: a severe variant of familial keloid scarring. J R Soc Med 96(11):554–555PubMedGoogle Scholar
  7. 7.
    Bayat A, Arscott G, Ollier WE, McGrouther DA, Ferguson MW (2005) Keloid disease: clinical relevance of single versus multiple site scars. Br J Plast Surg 58(1):28–37PubMedGoogle Scholar
  8. 8.
    Bayat A, Bock O, Mrowietz U, Ollier WE, Ferguson MW (2002) Genetic susceptibility to keloid disease and transforming growth factor beta 2 polymorphisms. Br J Plast Surg 55(4):283–286PubMedGoogle Scholar
  9. 9.
    Bayat A, Bock O, Mrowietz U, Ollier WE, Ferguson MW (2003) Genetic susceptibility to keloid disease and hypertrophic scarring: transforming growth factor beta1 common polymorphisms and plasma levels. Plast Reconstr Surg 111(2):535–543 (discussion 544–536)PubMedGoogle Scholar
  10. 10.
    Bayat A, Bock O, Mrowietz U, Ollier WE, Ferguson MW (2004) Genetic susceptibility to keloid disease: transforming growth factor beta receptor gene polymorphisms are not associated with keloid disease. Exp Dermatol 13(2):120–124PubMedGoogle Scholar
  11. 11.
    Bayat A, McGrouther DA, Ferguson MW (2003) Skin scarring. BMJ 326(7380):88–92PubMedGoogle Scholar
  12. 12.
    Bayat A, Walter JM, Bock O, Mrowietz U, Ollier WE, Ferguson MW (2005) Genetic susceptibility to keloid disease: mutation screening of the TGFbeta3 gene. Br J Plast Surg 58(7):914–921PubMedGoogle Scholar
  13. 13.
    Beanes SR, Hu FY, Soo C, Dang CM, Urata M, Ting K, Atkinson JB, Benhaim P, Hedrick MH, Lorenz HP (2002) Confocal microscopic analysis of scarless repair in the fetal rat: defining the transition. Plast Reconstr Surg 109(1):160–170PubMedGoogle Scholar
  14. 14.
    Berman B, Bieley HC (1996) Adjunct therapies to surgical management of keloids. Dermatol Surg 22(2):126–130PubMedGoogle Scholar
  15. 15.
    Bloom D (1956) Heredity of keloids; review of the literature and report of a family with multiple keloids in five generations. N Y State J Med 56(4):511–519PubMedGoogle Scholar
  16. 16.
    Boyce DE, Ciampolini J, Ruge F, Murison MS, Harding KG (2001) Inflammatory-cell subpopulations in keloid scars. Br J Plast Surg 54(6):511–516PubMedGoogle Scholar
  17. 17.
    Boyce DE, Jones WD, Ruge F, Harding KG, Moore K (2000) The role of lymphocytes in human dermal wound healing. Br J Dermatol 143(1):59–65PubMedGoogle Scholar
  18. 18.
    Brown BC, McKenna SP, Siddhi K, McGrouther DA, Bayat A (2008) The hidden cost of skin scars: quality of life after skin scarring. J Plast Reconstr Aesthet Surg 61(9):1049–1058PubMedGoogle Scholar
  19. 19.
    Brown JJ, Bayat A (2009) Genetic susceptibility to raised dermal scarring. Br J Dermatol 161(1):8–18PubMedGoogle Scholar
  20. 20.
    Brown JJ, Ollier W, Arscott G, Ke X, Lamb J, Day P, Bayat A (2008) Genetic susceptibility to keloid scarring: SMAD gene SNP frequencies in Afro-Caribbeans. Exp Dermatol 17(7):610–613PubMedGoogle Scholar
  21. 21.
    Brown JJ, Ollier W, Thomson W, Bayat A (2008) Positive association of HLA-DRB1*15 with Dupuytren’s disease in Caucasians. Tissue Antigens 72(2):166–170PubMedGoogle Scholar
  22. 22.
    Brown JJ, Ollier WE, Thomson W, Bayat A (2008) Positive association of HLA-DRB1*15 with keloid disease in Caucasians. Int J Immunogenet 35(4–5):303–307PubMedGoogle Scholar
  23. 23.
    Brown RL, Ormsby I, Doetschman TC, Greenhalgh DG (1995) Wound healing in the transforming growth factor-beta-deficient mouse. Wound Repair Regen 3(1):25–36PubMedGoogle Scholar
  24. 24.
    Butler PD, Longaker MT, Yang GP (2008) Current progress in keloid research and treatment. J Am Coll Surg 206(4):731–741PubMedGoogle Scholar
  25. 25.
    Char F (1971) Ehlers–Danlos syndrome. Birth Defects Orig Artic Ser 7(8):300–302PubMedGoogle Scholar
  26. 26.
    Chen W, Fu X, Sun X, Sun T, Zhao Z, Sheng Z (2003) Analysis of differentially expressed genes in keloids and normal skin with cDNA microarray. J Surg Res 113(2):208–216PubMedGoogle Scholar
  27. 27.
    Chen Y, Gao JH, Liu XJ, Yan X, Song M (2006) Characteristics of occurrence for Han Chinese familial keloids. Burns 32(8):1052–1059PubMedGoogle Scholar
  28. 28.
    Chen Y, Gao JH, Liu XJ, Yan X, Song M (2006) Linkage analysis of keloid susceptibility loci on chromosome 7p11 in a Chinese pedigree. Nan Fang Yi Ke Da Xue Xue Bao 26(5):623–625, 637Google Scholar
  29. 29.
    Chen Y, Gao JH, Yan X, Song M, Liu XJ (2007) Location of predisposing gene for one Han Chinese keloid pedigree. Zhonghua Zheng Xing Wai Ke Za Zhi 23(2):137–140PubMedGoogle Scholar
  30. 30.
    Chin GS, Liu W, Peled Z, Lee TY, Steinbrech DS, Hsu M, Longaker MT (2001) Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg 108(2):423–429PubMedGoogle Scholar
  31. 31.
    Chodon T, Sugihara T, Igawa HH, Funayama E, Furukawa H (2000) Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-beta1 can abrogate this resistance. Am J Pathol 157(5):1661–1669PubMedGoogle Scholar
  32. 32.
    Clark JA, Turner ML, Howard L, Stanescu H, Kleta R, Kopp JB (2009) Description of familial keloids in five pedigrees: evidence for autosomal dominant inheritance and phenotypic heterogeneity. BMC Dermatol 9:8PubMedGoogle Scholar
  33. 33.
    Craig SS, DeBlois G, Schwartz LB (1986) Mast cells in human keloid, small intestine, and lung by an immunoperoxidase technique using a murine monoclonal antibody against tryptase. Am J Pathol 124(3):427–435PubMedGoogle Scholar
  34. 34.
    Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: Database for annotation, visualization, and integrated discovery. Genome Biol 4(5):P3PubMedGoogle Scholar
  35. 35.
    Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584PubMedGoogle Scholar
  36. 36.
    Dienz O, Rincon M (2009) The effects of IL-6 on CD4 T cell responses. Clin Immunol 130(1):27–33Google Scholar
  37. 37.
    Dyment DA, Herrera BM, Cader MZ, Willer CJ, Lincoln MR, Sadovnick AD, Risch N, Ebers GC (2005) Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. Hum Mol Genet 14(14):2019–2026PubMedGoogle Scholar
  38. 38.
    Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, Simon RH (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97(1):232–237PubMedGoogle Scholar
  39. 39.
    Faler BJ, Macsata RA, Plummer D, Mishra L, Sidawy AN (2006) Transforming growth factor-beta and wound healing. Perspect Vasc Surg Endovasc Ther 18(1):55–62PubMedGoogle Scholar
  40. 40.
    Fattal PG, Schneider DJ, Sobel BE, Billadello JJ (1992) Post-transcriptional regulation of expression of plasminogen activator inhibitor type 1 mRNA by insulin and insulin-like growth factor 1. J Biol Chem 267(18):12412–12415PubMedGoogle Scholar
  41. 41.
    Fong EP, Bay BH (2002) Keloids—the sebum hypothesis revisited. Med Hypotheses 58(4):264–269PubMedGoogle Scholar
  42. 42.
    Frantz FW, Bettinger DA, Haynes JH, Johnson DE, Harvey KM, Dalton HP, Yager DR, Diegelmann RF, Cohen IK (1993) Biology of fetal repair: the presence of bacteria in fetal wounds induces an adult-like healing response. J Pediatr Surg 28(3):428–433 (discussion 433–424)PubMedGoogle Scholar
  43. 43.
    Friedman DW, Boyd CD, Mackenzie JW, Norton P, Olson RM, Deak SB (1993) Regulation of collagen gene expression in keloids and hypertrophic scars. J Surg Res 55(2):214–222PubMedGoogle Scholar
  44. 44.
    Fujiwara M, Muragaki Y, Ooshima A (2005) Upregulation of transforming growth factor-beta1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity. Arch Dermatol Res 297(4):161–169PubMedGoogle Scholar
  45. 45.
    Fukatsu A, Matsuo S, Yuzawa Y, Miyai H, Futenma A, Kato K (1993) Expression of interleukin 6 and major histocompatibility complex molecules in tubular epithelial cells of diseased human kidneys. Lab Invest 69(1):58–67Google Scholar
  46. 46.
    Ghazizadeh M (2007) Essential role of IL-6 signaling pathway in keloid pathogenesis. J Nippon Med Sch 74(1):11–22PubMedGoogle Scholar
  47. 47.
    Ghazizadeh M, Tosa M, Shimizu H, Hyakusoku H, Kawanami O (2007) Functional implications of the IL-6 signaling pathway in keloid pathogenesis. J Invest Dermatol 127(1):98–105PubMedGoogle Scholar
  48. 48.
    Goeminne L (1968) A new probably X-linked inherited syndrome: congenital muscular torticollis, multiple keloids cryptorchidism and renal dysplasia. Acta Genet Med Gemellol (Roma) 17(3):439–467Google Scholar
  49. 49.
    Gonzalez-Martinez R, Marin-Bertolin S, Amorrortu-Velayos J (1995) Association between keloids and Dupuytren’s disease: case report. Br J Plast Surg 48(1):47–48PubMedGoogle Scholar
  50. 50.
    Goodfellow A, Emmerson RW, Calvert HT (1980) Rubinstein–Taybi syndrome and spontaneous keloids. Clin Exp Dermatol 5(3):369–370PubMedGoogle Scholar
  51. 51.
    Guppy M (2002) The hypoxic core: a possible answer to the cancer paradox. Biochem Biophys Res Commun 299(4):676–680PubMedGoogle Scholar
  52. 52.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453(7193):314–321PubMedGoogle Scholar
  53. 53.
    Haisa M, Okochi H, Grotendorst GR (1994) Elevated levels of PDGF alpha receptors in keloid fibroblasts contribute to an enhanced response to PDGF. J Invest Dermatol 103(4):560–563PubMedGoogle Scholar
  54. 54.
    Hambrick GW Jr, Carter DM (1966) Pachydermoperiostosis. Touraine–Solente–Gole syndrome. Arch Dermatol 94(5):594–607PubMedGoogle Scholar
  55. 55.
    Heyen CA, Delk PR, Bull MJ, Weaver DD (2008) A report of an apparent new genetic syndrome consisting of joint contractures, keloids, large optic cup-to-disc ratio and renal stones. Am J Med Genet A 146A(24):3120–3125PubMedGoogle Scholar
  56. 56.
    Hocevar BA, Howe PH (2000) Analysis of TGF-beta-mediated synthesis of extracellular matrix components. Methods Mol Biol 142:55–65PubMedGoogle Scholar
  57. 57.
    Hu ZF, Gao JH, Li W, Song YB, Li CL (2006) Differential gene expression profile of keloids: a study with cDNA microarray. Nan Fang Yi Ke Da Xue Xue Bao 26(3):308–312PubMedGoogle Scholar
  58. 58.
    HuangDa W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57Google Scholar
  59. 59.
    Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J (2001) The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell 8(3):671–682PubMedGoogle Scholar
  60. 60.
    Ishihara H, Yoshimoto H, Fujioka M, Murakami R, Hirano A, Fujii T, Ohtsuru A, Namba H, Yamashita S (2000) Keloid fibroblasts resist ceramide-induced apoptosis by overexpression of insulin-like growth factor I receptor. J Invest Dermatol 115(6):1065–1071PubMedGoogle Scholar
  61. 61.
    Izzi L, Attisano L (2006) Ubiquitin-dependent regulation of TGFbeta signaling in cancer. Neoplasia 8(8):677–688PubMedGoogle Scholar
  62. 62.
    Jagadeesan J, Bayat A (2007) Transforming growth factor beta (TGFbeta) and keloid disease. Int J Surg 5(4):278–285PubMedGoogle Scholar
  63. 63.
    Kamamoto F, Paggiaro AO, Rodas A, Herson MR, Mathor MB, Ferreira MC (2003) A wound contraction experimental model for studying keloids and wound-healing modulators. Artif Organs 27(8):701–705PubMedGoogle Scholar
  64. 64.
    Kaminska B, Wesolowska A, Danilkiewicz M (2005) TGF beta signalling and its role in tumour pathogenesis. Acta Biochim Pol 52(2):329–337PubMedGoogle Scholar
  65. 65.
    Kang JS, Liu C, Derynck R (2009) New regulatory mechanisms of TGF-beta receptor function. Trends Cell Biol 19(8):385–394PubMedGoogle Scholar
  66. 66.
    Kikuchi K, Kadono T, Takehara K (1995) Effects of various growth factors and histamine on cultured keloid fibroblasts. Dermatology 190(1):4–8PubMedGoogle Scholar
  67. 67.
    Kischer CW (1992) The microvessels in hypertrophic scars, keloids and related lesions: a review. J Submicrosc Cytol Pathol 24(2):281–296PubMedGoogle Scholar
  68. 68.
    Kischer CW, Hendrix MJ (1983) Fibronectin (FN) in hypertrophic scars and keloids. Cell Tissue Res 231(1):29–37PubMedGoogle Scholar
  69. 69.
    Kischer CW, Thies AC, Chvapil M (1982) Perivascular myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Hum Pathol 13(9):819–824PubMedGoogle Scholar
  70. 70.
    Kohler HP, Grant PJ (2000) Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 342(24):1792–1801PubMedGoogle Scholar
  71. 71.
    Kuo YR, Wu WS, Wang FS (2007) Flashlamp pulsed-dye laser suppressed TGF-beta1 expression and proliferation in cultured keloid fibroblasts is mediated by MAPK pathway. Lasers Surg Med 39(4):358–364PubMedGoogle Scholar
  72. 72.
    Kurwa AR (1979) Rubinstein–Taybi syndrome and spontaneous keloids. Clin Exp Dermatol 4(2):251–254PubMedGoogle Scholar
  73. 73.
    Kutz SM, Hordines J, McKeown-Longo PJ, Higgins PJ (2001) TGF-beta1-induced PAI-1 gene expression requires MEK activity and cell-to-substrate adhesion. J Cell Sci 114(Pt 21):3905–3914Google Scholar
  74. 74.
    Ladin DA, Hou Z, Patel D, McPhail M, Olson JC, Saed GM, Fivenson DP (1998) p53 and apoptosis alterations in keloids and keloid fibroblasts. Wound Repair Regen 6(1):28–37PubMedGoogle Scholar
  75. 75.
    Lanning DA, Diegelmann RF, Yager DR, Wallace ML, Bagwell CE, Haynes JH (2000) Myofibroblast induction with transforming growth factor-beta1 and -beta3 in cutaneous fetal excisional wounds. J Pediatr Surg 35(2):183–187 (discussion 187–188)PubMedGoogle Scholar
  76. 76.
    Lee TY, Chin GS, Kim WJ, Chau D, Gittes GK, Longaker MT (1999) Expression of transforming growth factor beta 1, 2, and 3 proteins in keloids. Ann Plast Surg 43(2):179–184PubMedGoogle Scholar
  77. 77.
    LeFlore IC (1980) Misconceptions regarding elective plastic surgery in the black patient. J Natl Med Assoc 72(10):947–948PubMedGoogle Scholar
  78. 78.
    Li Y, Han B, Li K, Jiao LR, Habib N, Wang H (1999) TGF-beta 1 inhibits HLA-DR and beta 2-microglobulin expression in HeLa cells induced with r-IFN. Transplant Proc 31(5):2143–2145Google Scholar
  79. 79.
    Lijnen HR (2001) Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost 86(1):324–333PubMedGoogle Scholar
  80. 80.
    Lo TC, Seckel BR, Salzman FA, Wright KA (1990) Single-dose electron beam irradiation in treatment and prevention of keloids and hypertrophic scars. Radiother Oncol 19(3):267–272PubMedGoogle Scholar
  81. 81.
    Lopez-Casillas F, Wrana JL, Massague J (1993) Betaglycan presents ligand to the TGF beta signaling receptor. Cell 73(7):1435–1444PubMedGoogle Scholar
  82. 82.
    Lu WS, Wang JF, Yang S, Xiao FL, Quan C, Cheng H, Wang PG, Zhang AP, Cai LQ, Zhang XJ (2008) Association of HLA-DQA1 and DQB1 alleles with keloids in Chinese Hans. J Dermatol Sci 52(2):108–117PubMedGoogle Scholar
  83. 83.
    Maarouf M, Schleicher U, Schmachtenberg A, Ammon J (2002) Radiotherapy in the management of keloids. Clinical experience with electron beam irradiation and comparison with X-ray therapy. Strahlenther Onkol 178(6):330–335PubMedGoogle Scholar
  84. 84.
    Mandal A, Imran D, Rao GS (2004) Spontaneous keloids in siblings. Ir Med J 97(8):250–251PubMedGoogle Scholar
  85. 85.
    Marneros AG, Norris JE, Olsen BR, Reichenberger E (2001) Clinical genetics of familial keloids. Arch Dermatol 137(11):1429–1434PubMedGoogle Scholar
  86. 86.
    Marneros AG, Norris JE, Watanabe S, Reichenberger E, Olsen BR (2004) Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol 122(5):1126–1132PubMedGoogle Scholar
  87. 87.
    McCauley RL, Chopra V, Li YY, Herndon DN, Robson MC (1992) Altered cytokine production in black patients with keloids. J Clin Immunol 12(4):300–308PubMedGoogle Scholar
  88. 88.
    Meyer LJ, Russell SB, Russell JD, Trupin JS, Egbert BM, Shuster S, Stern R (2000) Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts. J Invest Dermatol 114(5):953–959PubMedGoogle Scholar
  89. 89.
    Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118(Pt 16):3573–3584PubMedGoogle Scholar
  90. 90.
    Muller-Hilke B (2009) HLA class II and autoimmunity: epitope selection vs differential expression. Acta Histochem 111(4):379–381PubMedGoogle Scholar
  91. 91.
    Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare PG, Stella M, Teot L, Wood FM, Ziegler UE (2002) International clinical recommendations on scar management. Plast Reconstr Surg 110(2):560–571PubMedGoogle Scholar
  92. 92.
    Na GY, Seo SK, Lee SJ, Kim DW, Kim MK, Kim JC (2004) Upregulation of the NNP-1 (novel nuclear protein-1, D21S2056E) gene in keloid tissue determined by cDNA microarray and in situ hybridization. Br J Dermatol 151(6):1143–1149PubMedGoogle Scholar
  93. 93.
    Naitoh M, Kubota H, Ikeda M, Tanaka T, Shirane H, Suzuki S, Nagata K (2005) Gene expression in human keloids is altered from dermal to chondrocytic and osteogenic lineage. Genes Cells 10(11):1081–1091PubMedGoogle Scholar
  94. 94.
    Nassiri M, Woolery-Lloyd H, Ramos S, Jacob SE, Gugic D, Viciana A, Romanelli P, Elgart G, Berman B, Vincek V (2009) Gene expression profiling reveals alteration of caspase 6 and 14 transcripts in normal skin of keloid-prone patients. Arch Dermatol Res 301(2):183–188PubMedGoogle Scholar
  95. 95.
    O’Sullivan ST, O’Shaughnessy M, O’Connor TP (1996) Aetiology and management of hypertrophic scars and keloids. Ann R Coll Surg Engl 78(3(Pt 1)):168–175PubMedGoogle Scholar
  96. 96.
    Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T (2003) Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: retrospective study of 147 cases followed for more than 18 months. Plast Reconstr Surg 111(2):547–553 (discussion 554–545)PubMedGoogle Scholar
  97. 97.
    Ohtsuru A, Yoshimoto H, Ishihara H, Namba H, Yamashita S (2000) Insulin-like growth factor-I (IGF-I)/IGF-I receptor axis and increased invasion activity of fibroblasts in keloid. Endocr J 47(Suppl):S41–S44PubMedGoogle Scholar
  98. 98.
    Omo-Dare P (1975) Genetic studies on keloid. J Natl Med Assoc 67(6):428–432PubMedGoogle Scholar
  99. 99.
    Peltonen J, Hsiao LL, Jaakkola S, Sollberg S, Aumailley M, Timpl R, Chu ML, Uitto J (1991) Activation of collagen gene expression in keloids: co-localization of type I and VI collagen and transforming growth factor-beta 1 mRNA. J Invest Dermatol 97(2):240–248PubMedGoogle Scholar
  100. 100.
    Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ et al (1995) Rubinstein–Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376(6538):348–351PubMedGoogle Scholar
  101. 101.
    Phan TT, Lim IJ, Aalami O, Lorget F, Khoo A, Tan EK, Mukhopadhyay A, Longaker MT (2005) Smad3 signalling plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions. J Pathol 207(2):232–242PubMedGoogle Scholar
  102. 102.
    Pohlers D, Brenmoehl J, Loffler I, Muller CK, Leipner C, Schultze-Mosgau S, Stallmach A, Kinne RW, Wolf G (2009) TGF-beta and fibrosis in different organs—molecular pathway imprints. Biochim Biophys Acta 1792(8):746–756PubMedGoogle Scholar
  103. 103.
    Pope FM, Martin GR, Lichtenstein JR, Penttinen R, Gerson B, Rowe DW, McKusick VA (1975) Patients with Ehlers–Danlos syndrome type IV lack type III collagen. Proc Natl Acad Sci USA 72(4):1314–1316PubMedGoogle Scholar
  104. 104.
    Pope FM, Martin GR, McKusick VA (1977) Inheritance of Ehlers–Danlos type IV syndrome. J Med Genet 14(3):200–204PubMedGoogle Scholar
  105. 105.
    Ramakrishnan KM, Thomas KP, Sundararajan CR (1974) Study of 1, 000 patients with keloids in South India. Plast Reconstr Surg 53(3):276–280PubMedGoogle Scholar
  106. 106.
    Reilly CF, McFall RC (1991) Platelet-derived growth factor and transforming growth factor-beta regulate plasminogen activator inhibitor-1 synthesis in vascular smooth muscle cells. J Biol Chem 266(15):9419–9427PubMedGoogle Scholar
  107. 107.
    Rojas A, Padidam M, Cress D, Grady WM (2009) TGF-beta receptor levels regulate the specificity of signaling pathway activation and biological effects of TGF-beta. Biochim Biophys Acta 1793(7):1165–1173PubMedGoogle Scholar
  108. 108.
    Saed GM, Ladin D, Olson J, Han X, Hou Z, Fivenson D (1998) Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing. Arch Dermatol 134(8):963–967PubMedGoogle Scholar
  109. 109.
    Satish L, Babu M, Tran KT, Hebda PA, Wells A (2004) Keloid fibroblast responsiveness to epidermal growth factor and activation of downstream intracellular signaling pathways. Wound Repair Regen 12(2):183–192PubMedGoogle Scholar
  110. 110.
    Satish L, Lyons-Weiler J, Hebda PA, Wells A (2006) Gene expression patterns in isolated keloid fibroblasts. Wound Repair Regen 14(4):463–470PubMedGoogle Scholar
  111. 111.
    Sato Y, Rifkin DB (1989) Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J Cell Biol 109(1):309–315PubMedGoogle Scholar
  112. 112.
    Sawdey MS, Loskutoff DJ (1991) Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest 88(4):1346–1353PubMedGoogle Scholar
  113. 113.
    Sayah DN, Soo C, Shaw WW, Watson J, Messadi D, Longaker MT, Zhang X, Ting K (1999) Downregulation of apoptosis-related genes in keloid tissues. J Surg Res 87(2):209–216PubMedGoogle Scholar
  114. 114.
    Seifert O, Bayat A, Geffers R, Dienus K, Buer J, Lofgren S, Matussek A (2008) Identification of unique gene expression patterns within different lesional sites of keloids. Wound Repair Regen 16(2):254–265PubMedGoogle Scholar
  115. 115.
    Seifert O, Mrowietz U (2009) Keloid scarring: bench and bedside. Arch Dermatol Res 301(4):259–272PubMedGoogle Scholar
  116. 116.
    Shah M, Foreman DM, Ferguson MW (1992) Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet 339(8787):213–214PubMedGoogle Scholar
  117. 117.
    Shah M, Foreman DM, Ferguson MW (1995) Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci 108(Pt 3):985–1002PubMedGoogle Scholar
  118. 118.
    Shang QX, Yuan R, Wang W (2000) Expression of platelet derived growth factor receptor-beta in fibroblasts of keloid. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 14(5):278–282PubMedGoogle Scholar
  119. 119.
    Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X (2004) GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol 164(2):291–300PubMedGoogle Scholar
  120. 120.
    Siraganian PA, Rubinstein JH, Miller RW (1989) Keloids and neoplasms in the Rubinstein–Taybi syndrome. Med Pediatr Oncol 17(6):485–491PubMedCrossRefGoogle Scholar
  121. 121.
    Smith JC, Boone BE, Opalenik SR, Williams SM, Russell SB (2008) Gene profiling of keloid fibroblasts shows altered expression in multiple fibrosis-associated pathways. J Invest Dermatol 128(5):1298–1310PubMedGoogle Scholar
  122. 122.
    Souchelnytskyi S, ten Dijke P, Miyazono K, Heldin CH (1996) Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses. EMBO J 15(22):6231–6240PubMedGoogle Scholar
  123. 123.
    Subramanian R, White CJ, Sternbergh WC III, Ferguson DL, Gilchrist IC (2003) Nonhealing wound resulting from a foreign-body reaction to a radial arterial sheath. Catheter Cardiovasc Interv 59(2):205–206PubMedGoogle Scholar
  124. 124.
    Teofoli P, Barduagni S, Ribuffo M, Campanella A, De Pita O, Puddu P (1999) Expression of Bcl-2, p53, c-jun and c-fos protooncogenes in keloids and hypertrophic scars. J Dermatol Sci 22(1):31–37PubMedGoogle Scholar
  125. 125.
    Toriseva M, Kahari VM (2009) Proteinases in cutaneous wound healing. Cell Mol Life Sci 66(2):203–224PubMedGoogle Scholar
  126. 126.
    Tosa M, Ghazizadeh M, Shimizu H, Hirai T, Hyakusoku H, Kawanami O (2005) Global gene expression analysis of keloid fibroblasts in response to electron beam irradiation reveals the involvement of interleukin-6 pathway. J Invest Dermatol 124(4):704–713PubMedGoogle Scholar
  127. 127.
    Tredget EE, Nedelec B, Scott PG, Ghahary A (1997) Hypertrophic scars, keloids, and contractures. The cellular and molecular basis for therapy. Surg Clin North Am 77(3):701–730PubMedGoogle Scholar
  128. 128.
    Tuan TL, Hwu P, Ho W, Yiu P, Chang R, Wysocki A, Benya PD (2008) Adenoviral overexpression and small interfering RNA suppression demonstrate that plasminogen activator inhibitor-1 produces elevated collagen accumulation in normal and keloid fibroblasts. Am J Pathol 173(5):1311–1325PubMedGoogle Scholar
  129. 129.
    Tuan TL, Nichter LS (1998) The molecular basis of keloid and hypertrophic scar formation. Mol Med Today 4(1):19–24PubMedGoogle Scholar
  130. 130.
    Tuan TL, Wu H, Huang EY, Chong SS, Laug W, Messadi D, Kelly P, Le A (2003) Increased plasminogen activator inhibitor-1 in keloid fibroblasts may account for their elevated collagen accumulation in fibrin gel cultures. Am J Pathol 162(5):1579–1589PubMedGoogle Scholar
  131. 131.
    Tuan TL, Zhu JY, Sun B, Nichter LS, Nimni ME, Laug WE (1996) Elevated levels of plasminogen activator inhibitor-1 may account for the altered fibrinolysis by keloid fibroblasts. J Invest Dermatol 106(5):1007–1011PubMedGoogle Scholar
  132. 132.
    Wang X, Smith P, Pu LL, Kim YJ, Ko F, Robson MC (1999) Exogenous transforming growth factor beta(2) modulates collagen I and collagen III synthesis in proliferative scar xenografts in nude rats. J Surg Res 87(2):194–200PubMedGoogle Scholar
  133. 133.
    Wang Z, Gao Z, Shi Y, Sun Y, Lin Z, Jiang H, Hou T, Wang Q, Yuan X, Zhu X et al (2007) Inhibition of Smad3 expression decreases collagen synthesis in keloid disease fibroblasts. J Plast Reconstr Aesthet Surg 60(11):1193–1199PubMedGoogle Scholar
  134. 134.
    Wu Y, Zhang Q, Ann DK, Akhondzadeh A, Duong HS, Messadi DV, Le AD (2004) Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts. Am J Physiol Cell Physiol 286(4):C905–C912PubMedGoogle Scholar
  135. 135.
    Xia W, Longaker MT, Yang GP (2006) P38 MAP kinase mediates transforming growth factor-beta2 transcription in human keloid fibroblasts. Am J Physiol Regul Integr Comp Physiol 290(3):R501–R508PubMedGoogle Scholar
  136. 136.
    Xia W, Phan TT, Lim IJ, Longaker MT, Yang GP (2006) Differential transcriptional responses of keloid and normal keratinocytes to serum stimulation. J Surg Res 135(1):156–163PubMedGoogle Scholar
  137. 137.
    Yan L, Lu XY, Wang CM, Cao R, Yin YH, Jia CS, Zhuang Q (2007) Association between p53 gene codon 72 polymorphism and keloid in Chinese population. Zhonghua Zheng Xing Wai Ke Za Zhi 23(5):428–430PubMedGoogle Scholar
  138. 138.
    Yan X, Gao JH, Chen Y, Song M, Liu XJ (2007) Preliminary linkage analysis and mapping of keloid susceptibility locus in a Chinese pedigree. Zhonghua Zheng Xing Wai Ke Za Zhi 23(1):32–35PubMedGoogle Scholar
  139. 139.
    Yoshimoto H, Ishihara H, Ohtsuru A, Akino K, Murakami R, Kuroda H, Namba H, Ito M, Fujii T, Yamashita S (1999) Overexpression of insulin-like growth factor-1 (IGF-I) receptor and the invasiveness of cultured keloid fibroblasts. Am J Pathol 154(3):883–889PubMedGoogle Scholar
  140. 140.
    Yu H, Bock O, Bayat A, Ferguson MW, Mrowietz U (2006) Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. J Plast Reconstr Aesthet Surg 59(3):221–229PubMedGoogle Scholar
  141. 141.
    Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14(2):163–176PubMedGoogle Scholar
  142. 142.
    Zhang G, Fu J, Luo S, Tang S, Liang L (2008) Relationship between mutation at 1,573 fragment of TNF receptor II gene and keloid. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 22(11):1311–1313PubMedGoogle Scholar
  143. 143.
    Zhang G, Jiang JJ, Luo SJ, Tang SM, Liang J, Yu Q (2008) The relationship between RUNX3 gene mutation and keloid. Zhonghua Zheng Xing Wai Ke Za Zhi 24(3):224–227PubMedGoogle Scholar
  144. 144.
    Zhang Q, Wu Y, Ann DK, Messadi DV, Tuan TL, Kelly AP, Bertolami CN, Le AD (2003) Mechanisms of hypoxic regulation of plasminogen activator inhibitor-1 gene expression in keloid fibroblasts. J Invest Dermatol 121(5):1005–1012PubMedGoogle Scholar
  145. 145.
    Zhang Q, Wu Y, Chau CH, Ann DK, Bertolami CN, Le AD (2004) Crosstalk of hypoxia-mediated signaling pathways in upregulating plasminogen activator inhibitor-1 expression in keloid fibroblasts. J Cell Physiol 199(1):89–97PubMedGoogle Scholar
  146. 146.
    Zhang Q, Yamaza T, Kelly AP, Shi S, Wang S, Brown J, Wang L, French SW, Le AD (2009) Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis. PLoS One 4(11):e7798PubMedGoogle Scholar
  147. 147.
    Zhuo Y, Gao J, Luo S, Zeng W, Hu Z, Lu F, Zhao Y (2005) p53 gene codon 72 polymorphism and susceptibility to keloid in Chinese population. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 19(1):28–30PubMedGoogle Scholar
  148. 148.
    Zhuo Y, Gao JH, Luo SQ, Zeng WS, Hu ZQ, Lu F, Zhao YZ (2005) p53 gene codon 72 polymorphism and susceptibility to keloid. Zhonghua Zheng Xing Wai Ke Za Zhi 21(3):201–203PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Plastic and Reconstructive Surgery Research, Epithelial Sciences, School of Translational Medicine, The Manchester Interdisciplinary Biocentre (MIB)University of ManchesterManchesterUK

Personalised recommendations