Advertisement

Fibrosing connective tissue disorders of the skin: Molecular similarities and distinctions

      Abstract

      A variety of fibrosing connective tissue disorders of the skin have been described. They all share a characteristic activation of fibroblasts resulting in excessive production and deposition of extracellular matrix whereas their etiologies, incidence rates and clinical appearances differ dramatically in part. As effective treatment options are still not on hand, the understanding of cutaneous fibrogenesis needs to be improved. This review focuses on the molecular differences and similarities of the major fibrosing skin disorders namely systemic sclerosis, localized scleroderma, keloid and hypertrophic scars, Eosinophilic fasciitis, Lichen sclerosus and graft-versus-host-disease. Abnormalities in ECM turnover and the impact of matrix-metalloproteases were closely examined. It could be concluded, that besides increased collagen synthesis, modified ECM degradation is an as important factor in cutaneous fibrogenesis. The influence of immune components such as HLA haplotypes and the production of auto-antibodies is crucial for some of the diseases, but not decisive for skin fibrosis in general. A great number of cytokines was reported to be differentially regulated in the respective disorders among whom the components of the gp130/STAT3 signaling pathway seem to be of pivotal importance. Furthermore, the role of miRNAs in the pathogenesis of fibrosing connective tissue diseases of the skin was analyzed according to the current state of knowledge.
      In summary, this review gives an explicit overview of the various molecular mechanisms leading to fibrosis in the skin and the underlying connective tissue and reveals the most promising targets for future therapeutic approaches.

      Keywords

      To read this article in full you will need to make a payment

      References

        • Zhu H.
        • Li Y.
        • Qu S.
        • Luo H.
        • Zhou Y.
        • Wang Y.
        • et al.
        MicroRNA expression abnormalities in limited cutaneous scleroderma and diffuse cutaneous scleroderma.
        J Clin Immunol. 2012; 32: 514-522
        • Medsger Jr., T.A.
        Epidemiology of systemic sclerosis.
        Clin Dermatol. 1994; 12: 207-216
        • Gilliam A.C.
        Scleroderma.
        Curr Dir Autoimmun. 2008; 10: 258-279
        • Tan F.K.
        • Wang N.
        • Kuwana M.
        • Chakraborty R.
        • Bona C.A.
        • Milewicz D.M.
        • et al.
        Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations.
        Arthritis Rheum. 2001; 44: 893-901
        • Genth E.
        • Krieg T.
        Systemic sclerosis – diagnosis and classification.
        Z Rheumatol. 2006; 65: 268-274
        • Fleming J.N.
        • Shulman H.M.
        • Nash R.A.
        • Johnson P.Y.
        • Wight T.N.
        • Gown A.
        • et al.
        Cutaneous chronic graft-versus-host disease does not have the abnormal endothelial phenotype or vascular rarefaction characteristic of systemic sclerosis.
        PLoS ONE. 2009; 4: e6203
        • Jinnin M.
        Mechanisms of skin fibrosis in systemic sclerosis.
        J Dermatol. 2010; 37: 11-25
        • Sato S.
        • Hayakawa I.
        • Hasegawa M.
        • Fujimoto M.
        • Takehara K.
        Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis.
        J Invest Dermatol. 2003; 120: 542-547
        • Nishijima C.
        • Hayakawa I.
        • Matsushita T.
        • Komura K.
        • Hasegawa M.
        • Takehara K.
        • et al.
        Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis.
        Clin Exp Immunol. 2004; 138: 357-363
        • Young-Min S.A.
        • Beeton C.
        • Laughton R.
        • Plumpton T.
        • Bartram S.
        • Murphy G.
        • et al.
        Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controls.
        Ann Rheum Dis. 2001; 60: 846-851
        • Nietert P.J.
        • Mitchell H.C.
        • Bolster M.B.
        • Shaftman S.R.
        • Tilley B.C.
        • Silver R.M.
        Racial variation in clinical and immunological manifestations of systemic sclerosis.
        J Rheumatol. 2006; 33: 263-268
        • Korn J.H.
        Scleroderma: a treatable disease.
        Cleve Clin J Med. 2003; 70 (958 passim): 954-956
        • Bhattacharyya S.
        • Wei J.
        • Varga J.
        Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities.
        Nat Rev Rheumatol. 2011; 8: 42-54
        • O’Reilly S.
        • Hügle T.
        • Van Laar J.M.
        T cells in systemic sclerosis: a reappraisal.
        Rheumatology (Oxford). 2012; 51: 1540-1549
        • Jun J.-B.
        • Kuechle M.
        • Min J.
        • Shim S.C.
        • Kim G.
        • Montenegro V.
        • et al.
        Scleroderma fibroblasts demonstrate enhanced activation of Akt (protein kinase B) in situ.
        J Invest Dermatol. 2005; 124: 298-303
        • Khan K.
        • Xu S.
        • Nihtyanova S.
        • Derrett-Smith E.
        • Abraham D.
        • Denton C.P.
        • et al.
        Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis.
        Ann Rheum Dis. 2012; 71: 1235-1242
        • O’Donoghue R.J.J.
        • Knight D.A.
        • Richards C.D.
        • Prêle C.M.
        • Lau H.L.
        • Jarnicki A.G.
        • et al.
        Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis.
        EMBO Mol Med. 2012; 4: 939-951
        • Avouac J.
        • Fürnrohr B.G.
        • Tomcik M.
        • Palumbo K.
        • Zerr P.
        • Horn A.
        • et al.
        Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis.
        Arthritis Rheum. 2011; 63: 800-809
        • Karrer S.
        • Bosserhoff A.K.
        • Weiderer P.
        • Distler O.
        • Landthaler M.
        • Szeimies R.-M.
        • et al.
        The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis.
        J Invest Dermatol. 2005; 124: 92-98
        • Romano E.
        • Manetti M.
        • Guiducci S.
        • Ceccarelli C.
        • Allanore Y.
        • Matucci-Cerinic M.
        The genetics of systemic sclerosis: an update.
        Clin Exp Rheumatol. 2011; 29: S75-S86
        • Arnett F.C.
        • Gourh P.
        • Shete S.
        • Ahn C.W.
        • Honey R.E.
        • Agarwal S.K.
        • et al.
        Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls.
        Ann Rheum Dis. 2010; 69: 822-827
        • Maurer B.
        • Stanczyk J.
        • Jüngel A.
        • Akhmetshina A.
        • Trenkmann M.
        • Brock M.
        • et al.
        MicroRNA-29, a key regulator of collagen expression in systemic sclerosis.
        Arthritis Rheum. 2010; 62: 1733-1743
        • Honda N.
        • Jinnin M.
        • Kajihara I.
        • Makino T.
        • Makino K.
        • Masuguchi S.
        • et al.
        TGF-β-mediated downregulation of MicroRNA-196a contributes to the constitutive upregulated type I collagen expression in scleroderma dermal fibroblasts.
        J Immunol. 2012; 188: 3323-3331
        • Clark S.
        Animal models in scleroderma.
        Curr Rheumatol Rep. 2005; 7: 150-155
        • Smith G.P.
        • Chan E.S.L.
        Molecular pathogenesis of skin fibrosis: insight from animal models.
        Curr Rheumatol Rep. 2010; 12: 26-33
        • Fett N.
        • Werth V.P.
        Update on morphea: part I. Epidemiology, clinical presentation, and pathogenesis.
        J Am Acad Dermatol. 2011; 64 ([quiz 229–30]): 217-228
        • Takehara K.
        • Sato S.
        Localized scleroderma is an autoimmune disorder.
        Rheumatology (Oxford). 2005; 44: 274-279
        • Leitenberger J.J.
        • Cayce R.L.
        • Haley R.W.
        • Adams-Huet B.
        • Bergstresser P.R.
        • Jacobe H.T.
        Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases.
        Arch Dermatol. 2009; 145: 545-550
        • Torres J.E.
        • Sánchez J.L.
        Histopathologic differentiation between localized and systemic scleroderma.
        Am J Dermatopathol. 1998; 20: 242-245
        • Kurzinski K.
        • Torok K.S.
        Cytokine profiles in localized scleroderma and relationship to clinical features.
        Cytokine. 2011; 55: 157-164
        • Passos C.O.
        • Werneck C.C.
        • Onofre G.R.
        • Pagani E.A.
        • Filgueira A.L.
        • Silva L.-C.
        Comparative biochemistry of human skin: glycosaminoglycans from different body sites in normal subjects and in patients with localized scleroderma.
        J Eur Acad Dermatol Venereol. 2003; 17: 14-19
        • Tomimura S.
        • Ogawa F.
        • Iwata Y.
        • Komura K.
        • Hara T.
        • Muroi E.
        • et al.
        Autoantibodies against matrix metalloproteinase-1 in patients with localized scleroderma.
        J Dermatol Sci. 2008; 52: 47-54
        • Satish L.
        • Lyons-Weiler J.
        • Hebda P.A.
        • Wells A.
        Gene expression patterns in isolated keloid fibroblasts.
        Wound Repair Regen. 2006; 14: 463-470
        • Verhaegen P.D.H.M.
        • Van Zuijlen P.P.M.
        • Pennings N.M.
        • Van Marle J.
        • Niessen F.B.
        • Van Der Horst C.M.A.M.
        • et al.
        Differences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: an objective histopathological analysis.
        Wound Repair Regen. 2009; 17: 649-656
        • Meyer L.J.
        • Russell S.B.
        • Russell J.D.
        • Trupin J.S.
        • Egbert B.M.
        • Shuster S.
        • et al.
        Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts.
        J Invest Dermatol. 2000; 114: 953-959
        • Chipev C.C.
        • Simman R.
        • Hatch G.
        • Katz A.E.
        • Siegel D.M.
        • Simon M.
        Myofibroblast phenotype and apoptosis in keloid and palmar fibroblasts in vitro.
        Cell Death Differ. 2000; 7: 166-176
        • Ulrich D.
        • Ulrich F.
        • Unglaub F.
        • Piatkowski A.
        • Pallua N.
        Matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with different types of scars and keloids.
        J Plast Reconstr Aesthet Surg. 2010; 63: 1015-1021
        • Brown J.J.
        • Ollier W.E.R.
        • Thomson W.
        • Bayat A.
        Positive association of HLA-DRB1*15 with keloid disease in Caucasians.
        Int J Immunogenet. 2008; 35: 303-307
        • Seifert O.
        • Mrowietz U.
        Keloid scarring: bench and bedside.
        Arch Dermatol Res. 2009; 301: 259-272
        • Lim C.P.
        • Phan T.-T.
        • Lim I.J.
        • Cao X.
        Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration.
        Oncogene. 2006; 25: 5416-5425
        • Ghazizadeh M.
        • Tosa M.
        • Shimizu H.
        • Hyakusoku H.
        • Kawanami O.
        Functional implications of the IL-6 signaling pathway in keloid pathogenesis.
        J Invest Dermatol. 2007; 127: 98-105
        • Brown J.J.
        • Ollier W.
        • Arscott G.
        • Ke X.
        • Lamb J.
        • Day P.
        • et al.
        Genetic susceptibility to keloid scarring: SMAD gene SNP frequencies in Afro-Caribbeans.
        Exp Dermatol. 2008; 17: 610-613
        • Nakashima M.
        • Chung S.
        • Takahashi A.
        • Kamatani N.
        • Kawaguchi T.
        • Tsunoda T.
        • et al.
        A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population.
        Nat Genet. 2010; 42: 768-771
        • Kashiyama K.
        • Mitsutake N.
        • Matsuse M.
        • Ogi T.
        • Saenko V.A.
        • Ujifuku K.
        • et al.
        miR-196a downregulation increases the expression of Type I and III collagens in keloid fibroblasts.
        J Invest Dermatol. 2012; 132: 1597-1604
        • Liu Y.
        • Yang D.
        • Xiao Z.
        • Zhang M.
        miRNA expression profiles in keloid tissue and corresponding normal skin tissue.
        Aesthetic Plast Surg. 2012; 36: 193-201
        • Wang H.
        • Luo S.
        Establishment of an animal model for human keloid scars using tissue engineering method.
        J Burn Care Res. 2012; ([Epub ahead of print])
        • Mahdavian Delavary B.
        • Van der Veer W.M.
        • Ferreira J.A.
        • Niessen F.B.
        Formation of hypertrophic scars: evolution and susceptibility.
        J Plast Surg Hand Surg. 2012; 46: 95-101
        • Gabriel V.
        Hypertrophic scar.
        Phys Med Rehabil Clin N Am. 2011; 22: 301-310
        • Bock O.
        • Yu H.
        • Zitron S.
        • Bayat A.
        • Ferguson M.W.J.
        • Mrowietz U.
        Studies of transforming growth factors beta 1–3 and their receptors I and II in fibroblast of keloids and hypertrophic scars.
        Acta Derm Venereol. 2005; 85: 216-220
        • Cheng B.
        • Fu X.
        • Sun T.
        • Sun X.
        • Sheng Z.
        Expression of epidermal growth factor receptor and related phosphorylation proteins in hypertrophic scars and normal skin.
        Chin Med J. 2002; 115: 1525-1528
        • Laurentaci G.
        • Dioguardi D.
        HLA antigens in keloids and hypertrophic scars.
        Arch Dermatol. 1977; 113: 1726
        • McCarty S.M.
        • Syed F.
        • Bayat A.
        Influence of the human leukocyte antigen complex on the development of cutaneous fibrosis: an immunogenetic perspective.
        Acta Derm Venereol. 2010; 90: 563-574
        • Ramos M.L.C.
        • Gragnani A.
        • Ferreira L.M.
        Is there an ideal animal model to study hypertrophic scarring?.
        J Burn Care Res. 2008; 29: 363-368
        • Momtazi M.
        • Kwan P.
        • Ding J.
        • Anderson C.C.
        • Honardoust D.
        • Goekjian S.
        • et al.
        A nude mouse model of hypertrophic scar shows morphologic and histologic characteristics of human hypertrophic scar.
        Wound Repair Regen. 2013; 21: 77-87
        • Bischoff L.
        • Derk C.T.
        Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review of the literature.
        Int J Dermatol. 2008; 47: 29-35
        • Kähäri V.M.
        • Heino J.
        • Niskanen L.
        • Fräki J.
        • Uitto J.
        Eosinophilic fasciitis. Increased collagen production and type I procollagen messenger RNA levels in fibroblasts cultured from involved skin.
        Arch Dermatol. 1990; 126: 613-617
        • Jinnin M.
        • Ihn H.
        • Yamane K.
        • Asano Y.
        • Yazawa N.
        • Tamaki K.
        Serum levels of tissue inhibitor of metalloproteinase-1 and 2 in patients with eosinophilic fasciitis.
        Br J Dermatol. 2004; 151: 407-412
        • Lakhanpal S.
        • Ginsburg W.W.
        • Michet C.J.
        • Doyle J.A.
        • Moore S.B.
        Eosinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases.
        Semin Arthritis Rheum. 1988; 17: 221-231
        • Dziadzio L.
        • Kelly E.A.
        • Panzer S.E.
        • Jarjour N.
        • Huttenlocher A.
        Cytokine abnormalities in a patient with eosinophilic fasciitis.
        Ann Allergy Asthma Immunol. 2003; 90: 452-455
        • Anderson S.T.
        • Klein E.C.
        Eosinophilic fasciitis in a rhesus macaque.
        Arthritis Rheum. 1992; 35: 714-716
        • Powell J.J.
        • Wojnarowska F.
        Lichen sclerosus.
        Lancet. 1999; 353: 1777-1783
        • Neill S.M.
        • Lewis F.M.
        • Tatnall F.M.
        • Cox N.H.
        British Association of Dermatologists’ guidelines for the management of lichen sclerosus 2010.
        Br J Dermatol. 2010; 163: 672-682
        • Aynaud O.
        • Piron D.
        • Casanova J.M.
        Incidence of preputial lichen sclerosus in adults: histologic study of circumcision specimens.
        J Am Acad Dermatol. 1999; 41: 923-926
        • Walkden
        • Yoon Chia Fenella Wojnarow V.
        The association of squamous cell carcinoma of the vulva and lichen sclerosus: implications for management and follow up.
        J Obstet Gynaecol. 1997; 17: 551-553
        • Val I.
        • Almeida G.
        An overview of lichen sclerosus.
        Clin Obstet Gynecol. 2005; 48: 808-817
        • De Oliveira G.A.P.
        • De Almeida M.P.
        • Soares F.A.
        • De Almeida Filho G.L.
        • Takiya C.M.
        • Otazu I.B.
        • et al.
        Metalloproteinases 2 and 9 and their tissue inhibitors 1 and 2 are increased in vulvar lichen sclerosus.
        Eur J Obstet Gynecol Reprod Biol. 2012; 161: 96-101
        • Powell J.
        • Wojnarowska F.
        • Winsey S.
        • Marren P.
        • Welsh K.
        Lichen sclerosus premenarche: autoimmunity and immunogenetics.
        Br J Dermatol. 2000; 142: 481-484
        • Birenbaum D.L.
        • Young R.C.
        High prevalence of thyroid disease in patients with lichen sclerosus.
        J Reprod Med. 2007; 52: 28-30
        • Oyama N.
        • Chan I.
        • Neill S.
        • Hamada T.
        • South A.
        • Wessagowit V.
        • et al.
        Autoantibodies to extracellular matrix protein 1 in lichen sclerosus.
        Lancet. 2003; 362: 118-123
        • Edmonds E.V.J.
        • Oyama N.
        • Chan I.
        • Francis N.
        • McGrath J.A.
        • Bunker C.B.
        Extracellular matrix protein 1 autoantibodies in male genital lichen sclerosus.
        Br J Dermatol. 2011; 165: 218-219
        • Pugliese J.M.
        • Morey A.F.
        • Peterson A.C.
        Lichen sclerosus: review of the literature and current recommendations for management.
        J Urol. 2007; 178: 2268-2276
        • Gao X.-H.
        • Barnardo M.C.M.N.
        • Winsey S.
        • Ahmad T.
        • Cook J.
        • Agudelo J.D.
        • et al.
        The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/DQB10201/02/03 haplotype protects from vulval lichen sclerosus.
        J Invest Dermatol. 2005; 125: 895-899
        • Clay F.E.
        • Tarlow J.K.
        • Cork M.J.
        • Cox A.
        • Nicklin M.J.
        • Duff G.W.
        Novel interleukin-1 receptor antagonist exon polymorphisms and their use in allele-specific mRNA assessment.
        Hum Genet. 1996; 97: 723-726
        • Farrell A.M.
        • Dean D.
        • Millard P.R.
        • Charnock F.M.
        • Wojnarowska F.
        Cytokine alterations in lichen sclerosus: an immunohistochemical study.
        Br J Dermatol. 2006; 155: 931-940
        • Terlou A.
        • Santegoets L.A.M.
        • Van der Meijden W.I.
        • Heijmans-Antonissen C.
        • Swagemakers S.M.A.
        • Van der Spek P.J.
        • et al.
        An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155.
        J Invest Dermatol. 2012; 132: 658-666
        • Martires K.J.
        • Baird K.
        • Steinberg S.M.
        • Grkovic L.
        • Joe G.O.
        • Williams K.M.
        • et al.
        Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease.
        Blood. 2011; 118: 4250-4257
        • Fimiani M.
        • De Aloe G.
        • Cuccia A.
        Chronic graft versus host disease and skin.
        J Eur Acad Dermatol Venereol. 2003; 17: 512-517
        • Koreth J.
        • Matsuoka K.
        • Kim H.T.
        • McDonough S.M.
        • Bindra B.
        • Alyea 3rd, E.P.
        • et al.
        Interleukin-2 and regulatory T cells in graft-versus-host disease.
        N Engl J Med. 2011; 365: 2055-2066
        • Chiang K.-Y.
        • Abhyankar S.
        • Bridges K.
        • Godder K.
        • Henslee-Downey J.P.
        Recombinant human tumor necrosis factor receptor fusion protein as complementary treatment for chronic graft-versus-host disease.
        Transplantation. 2002; 73: 665-667
        • Ma H.-H.
        • Ziegler J.
        • Li C.
        • Sepulveda A.
        • Bedeir A.
        • Grandis J.
        • et al.
        Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3.
        Cell Immunol. 2011; 268: 37-46
        • Salmela M.T.
        • Karjalainen-Lindsberg M.L.
        • Jeskanen L.
        • Saarialho-Kere U.
        Overexpression of tissue inhibitor of metalloproteinases-3 in intestinal and cutaneous lesions of graft-versus-host disease.
        Mod Pathol. 2003; 16: 108-114
        • Espinoza J.L.
        • Takami A.
        • Nakata K.
        • Onizuka M.
        • Kawase T.
        • Akiyama H.
        • et al.
        A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation.
        PLoS ONE. 2011; 6: e26229
        • Broen K.
        • Van der Waart A.B.
        • Greupink-Draaisma A.
        • Metzig J.
        • Feuth T.
        • Schaap N.P.M.
        • et al.
        Polymorphisms in CCR6 are associated with chronic graft-versus-host disease and invasive fungal disease in matched-related hematopoietic stem cell transplantation.
        Biol Blood Marrow Transplant. 2011; 17: 1443-1449
        • Arora M.
        • Lindgren B.
        • Basu S.
        • Nagaraj S.
        • Gross M.
        • Weisdorf D.
        • et al.
        Polymorphisms in the base excision repair pathway and graft-versus-host disease.
        Leukemia. 2010; 24: 1470-1475
        • Ranganathan P.
        • Heaphy C.E.A.
        • Costinean S.
        • Stauffer N.
        • Na C.
        • Hamadani M.
        • et al.
        Regulation of acute graft-versus-host disease by microRNA-155.
        Blood. 2012; 119: 4786-4797
        • Schroeder M.A.
        • DiPersio J.F.
        Mouse models of graft-versus-host disease: advances and limitations.
        Dis Model Mech. 2011; 4: 318-333
        • Varga J.
        • Pasche B.
        Transforming growth factor beta as a therapeutic target in systemic sclerosis.
        Nat Rev Rheumatol. 2009; 5: 200-206
        • Ma L.
        • Zhuang S.
        The Role of STAT 3 in Tissue Fibrosis.
        Curr Chem Biol. 2011; 5: 44-51