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Scleroderma: recent lessons from murine models and implications for future therapeutics

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Pages 527-539 | Published online: 10 Jan 2014

References

  • LeRoy EC, Black C, Fleischmajer R et al. Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J. Rheumatol. 15, 202–205 (1988).
  • Furst DE, Clements PJ. Hypothesis for the pathogenesis of systemic sclerosis. J. Rheumatol. 24 ( Suppl. 48), 53–57 (1997).
  • 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. 82, 493–512 (1976).
  • Baxter RM, Crowell TP, McCrann ME, Frew EM, Gardner H. Analysis of the tight skin (Tsk1/+) mouse as a model for testing antifibrotic agents. Lab. Invest. 85, 1199–1209 (2005).
  • Menton DN, Hess RA, Lichtenstein JR, Eisen A. The structure and tensile properties of the skin of tight-skin (Tsk) mutant mice. J. Invest. Dermatol. 70, 4–10 (1978).
  • 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. 109, 1453–1462 (2002).
  • Hasegawa M, Hamaguchi Y, Yanaba K et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am. J. Pathol. 169, 954–966 (2006).
  • Matsushita T, Fujimoto M, Hasegawa M et al. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J. Invest. Dermatol. 127, 2772–2780 (2007).
  • LeRoy EC, Smith EA, Kahaleh MB, Trojanowska M, Silver RM. A strategy for determining the pathogenesis of systemic sclerosis: is transforming growth factor β the answer? Arthritis Rheum. 32, 817–825 (1989).
  • Sonnylal S, Denton CP, Zheng B et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum. 56, 334–344 (2007).
  • Denton CP, Zheng B, Shiwen X et al. Activation of a fibroblast-specific enhancer of the proalpha2(I) collagen gene in tight-skin mice. Arthritis Rheum. 44, 712–722 (2001).
  • Denton CP, Zheng B, Evans LA et al. Fibroblast-specific expression of a kinase-deficient type II transforming growth factor beta (TGFbeta) receptor leads to paradoxical activation of TGFbeta signaling pathways with fibrosis in transgenic mice. J. Biol. Chem. 278, 25109–25119 (2003).
  • Derrett-Smith EC, Dooley A, Khan K, Shi-wen X, Abraham D, Denton CP. Systemic vasculopathy with altered vasoreactivity in a transgenic mouse model of scleroderma. Arthritis Res. Ther. 12, R69 (2010).
  • Thoua NM, Derrett-Smith EC, Khan K, Dooley A, Shi-Wen X, Denton CP. Gut fibrosis with altered colonic contractility in a mouse model of scleroderma. Rheumatology (Oxford) 51, 1989–1998 (2012).
  • Asano Y, Markiewicz M, Kubo M, Szalai G, Watson DK, Trojanowska M. Transcription factor Fli1 regulates collagen fibrillogenesis in mouse skin. Mol. Cell. Biol. 29, 425–434 (2009).
  • Asano Y, Stawski L, Hant F et al. Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy. Am. J. Pathol. 176, 1983–1998.
  • Wagner EF, Eferl, R. 2005. Fos/AP-1 proteins in bone and the immune system. Immunol. Rev. 208, 126–140 (2010).
  • Eferl R, Hasselblatt P, Rath M et al. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc. Natl Acad. Sci. USA 105, 10525–10530 (2008).
  • Maurer B, Busch N, Jungel A et al. Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis. Circulation 120, 2367–2376 (2009).
  • Maurer B, Reich N, Juengel A et al. Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Ann. Rheum. Dis. 71, 1382–1387 (2012).
  • Reich N, Maurer B, Akhmetshina A et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum. 62, 280–290 (2010).
  • Razani B, Engelman JA, Wang XB et al. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J. Biol. Chem. 276, 38121–38138 (2001).
  • Drab M, Verkade P, Elger M et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293, 2449–2452 (2001).
  • Zhao YY, Liu Y, Stan RV et al. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc. Natl Acad. Sci. USA 99, 11375–11380 (2002).
  • Del Galdo F, Sotgia F, de Almeida CJ et al. Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis. Arthritis Rheum. 58, 2854–2865 (2008).
  • Yamamoto T, Takagawa S, Katayama I et al. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J. Invest. Dermatol. 112, 456–462 (1999).
  • Finch WR, Rodnan GP, Buckingham RB, Prince RK, Winkelstein A. Bleomycin-induced scleroderma. J. Rheumatol. 7, 651–659 (1980).
  • Yamamoto T, Nishioka K. Cellular and molecular mechanisms of bleomycin-induced murine scleroderma: current update and future perspective. Exp. Dermatol. 14, 81–95 (2005).
  • Yoshizaki A, Iwata Y, Komura K et al. CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol 172, 1650–1663 (2008).
  • Ishikawa H, Takeda K, Okamoto A, Matsuo S, Isobe K. Induction of autoimmunity in a bleomycin-induced murine model of experimental systemic sclerosis: an important role for CD4+ T cells. J. Invest. Dermatol. 129, 1688–1695 (2009).
  • Tanaka C, Fujimoto M, Hamaguchi Y, Sato S, Takehara K, Hasegawa M. Inducible costimulator ligand regulates bleomycin-induced lung and skin fibrosis in a mouse model independently of the inducible costimulator/inducible costimulator ligand pathway. Arthritis Rheum. 62, 1723–1732 (2010).
  • Yamamoto T, Katayama I. Vascular changes in bleomycin-induced scleroderma. Int. J. Rheumatol. 2011, 270938 (2011).
  • 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. 44, 2653–2664 (2001).
  • Simonini G, Cerinic MM, Generini S et al. Oxidative stress in Systemic Sclerosis. Mol. Cell Biochem. 196, 85–91 (1999).
  • Kavian, N, Servettaz, A, Mongaret, C et al. Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum. 62, 3477–3487 (2010).
  • Svegliati S, Cancello R, Sambo P et al. Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2. Amplification of ROS and Ras in systemic sclerosis fibroblasts. J. Biol. Chem. 280, 36474–36482 (2005).
  • Casciola-Rosen L, Wigley F, Rosen A. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J. Exp. Med. 185, 71–79 (1997).
  • Servettaz A, Goulvestre C, Kavian N et al. Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse. J. Immunol. 182, 5855–5864 (2009).
  • Mori T, Kawara S, Shinozaki M et al. Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: a mouse fibrosis model. J. Cell Physiol. 181, 153–159 (1999).
  • Chujo S, Shirasaki F, Kawara S et al. Connective tissue growth factor causes persistent proalpha2(I) collagen gene expression induced by transforming growth factor-beta in a mouse fibrosis model. J. Cell Physiol. 203, 447–456 (2005).
  • Arai M, Ikawa Y, Chujo S et al. Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis. J. Dermatol. Sci. 69(3), 250–258 (2012).
  • Ikawa Y, Ng PS, Endo K et al. Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-beta-induced mouse fibrosis. J. Cell Physiol. 216, 680–687 (2008).
  • Yamamoto T. Characteristics of Animal Models for Scleroderma. Curr. Rheumatol. Rev. 1, 101–109 (2005).
  • Claman HN, Jaffee BD, Huff JC, Clark RA. Chronic graft-versus-host disease as a model for scleroderma. II. Mast cell depletion with deposition of immunoglobulins in the skin and fibrosis. Cell Immunol. 94, 73–84 (1985).
  • Anderson BE, McNiff J, Yan J et al. Memory CD4+ T cells do not induce graft-versus-host disease. J. Clin. Invest. 112, 101–108 (2003).
  • Ruzek MC, Jha S, Ledbetter S, Richards SM, Garman RD. A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease. Arthritis Rheum. 50, 1319–1331 (2004).
  • Matte-Martone C, Wang X, Anderson B et al. Recipient B cells are not required for graft-versus-host disease induction. Biol. Blood Marrow Transplant. 16, 1222–1230 (2010).
  • Le Huu D, Matsushita T, Jin G et al. Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease. Blood 121(16), 3274–3283 (2013).
  • Asano Y. Future treatments in systemic sclerosis. J. Dermatol. 37, 54–70 (2010).
  • Denton CP, Merkel PA, Furst DE et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56, 323–333 (2007).
  • McCormick LL, Zhang Y, Tootell E, Gilliam AC. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J. Immunol. 163, 5693–5699 (1999).
  • Santiago B, Gutierrez-Canas I, Dotor J et al. Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis. J. Invest. Dermatol. 125, 450–455 (2005).
  • Nakamura-Wakatsuki T, Oyama N, Yamamoto T. Local injection of latency-associated peptide, a linker propeptide specific for active form of transforming growth factor-beta1, inhibits dermal sclerosis in bleomycin-induced murine scleroderma. Exp. Dermatol. 21, 189–194 (2012).
  • Vorstenbosch J, Al-Ajmi H, Winocour S, Trzeciak A, Lessard L, Philip A. CD109 overexpression ameliorates skin fibrosis in a bleomycin-induced mouse model of scleroderma. Arthritis Rheum. (2013).
  • 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. 60, 3465–3475 (2009).
  • Dooley S, Said HM, Gressner AM, Floege J, En-Nia A, Mertens PR. Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects. J. Biol. Chem. 281, 1784–1795 (2006).
  • Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H, Nakatsuka I. Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction of YB-1 with Smad3. J. Biol. Chem. 278, 43470–43479 (2003).
  • Jochum W, Passegue E, Wagner EF. AP-1 in mouse development and tumorigenesis. Oncogene 20, 2401–2412 (2001).
  • Verrecchia F, Vindevoghel L, Lechleider RJ, Uitto J, Roberts AB, Mauviel, A. Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner. Oncogene 20, 3332–3340 (2001).
  • Palumbo K, Zerr P, Tomcik M et al. The transcription factor JunD mediates transforming growth factor β-induced fibroblast activation and fibrosis in systemic sclerosis. Ann. Rheum. Dis. 70, 1320–1326 (2011).
  • Avouac J, Palumbo K, Tomcik M et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor beta-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum. 64, 1642–1652 (2012).
  • Varga JA, Trojanowska M. Fibrosis in systemic sclerosis. Rheum. Dis. Clin. North Am. 34, 115–143 (2008).
  • Daniels CE, Wilkes MC, Edens M et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J. Clin. Invest. 114, 1308–1316 (2004).
  • 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. 60, 219–224 (2009).
  • Distler JH, Jungel A, Huber LC et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum. 56, 311–322 (2007).
  • Prey S, Ezzedine K, Doussau A et al. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br. J. Dermatol. 167, 1138–1144 (2012).
  • Akhmetshina A, Dees C, Pileckyte, M et al. Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J. 22, 2214–2222 (2008).
  • Kavian N, Servettaz A, Marut W et al. Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor beta in the skin of mice with scleroderma-like features and prevents the development of the disease. Arthritis Rheum. 64, 1990–2000 (2012).
  • Pendergrass SA, Hayes E, Farina G et al. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS ONE 5, e12106 (2010).
  • Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 112, 3959–3964 (2008).
  • Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu. Rev. Pharmacol. Toxicol. 52, 199–219 (2012).
  • Le Huu D, Matsushita T, Jin G et al. IL-6 blockade attenuates the development of murine sclerodermatous chronic graft-versus-host disease. J. Invest. Dermatol. 132, 2752–2761 (2012).
  • Kitaba S, Murota H, Terao M et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am. J. Pathol. 180, 165–176 (2012).
  • Shima Y, Kuwahara Y, Murota H et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford) 49, 2408–2412 (2010).
  • Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavell RA, Li M. O. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation. Immunity 34, 396–408 (2011).
  • Radstake TR, van Bon L, Broen J et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNγ distinguishes SSc phenotypes. PLoS ONE 4, e5903 (2009).
  • Murata M, Fujimoto M, Matsushita T et al. Clinical association of serum interleukin-17 levels in systemic sclerosis: is systemic sclerosis a Th17 disease? J. Dermatol. Sci. 50, 240–242 (2008).
  • Nakashima T, Jinnin M, Yamane K et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J. Immunol. 188, 3573–3583 (2012).
  • Yoshizaki A, Yanaba K, Iwata Y et al. Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model. J. Immunol. 185, 2502–2515 (2010).
  • Okamoto Y, Hasegawa M, Matsushita T et al. Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis Rheum. 64, 3726–3735 (2012).
  • Hill GR, Olver SD, Kuns RD et al. Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma. Blood 116, 819–828 (2010).
  • Bonniaud P, Margetts PJ, Ask K, Flanders K, Gauldie J, Kolb M. TGF-beta and Smad3 signaling link inflammation to chronic fibrogenesis. J. Immunol. 175, 5390–5395 (2005).
  • Greenblatt MB, Sargent JL, Farina G et al. Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. Am. J. Pathol. 180, 1080–1094 (2012).
  • Bosello S, De Luca G, Tolusso B et al. B cells in systemic sclerosis: a possible target for therapy. Autoimmun Rev. 10, 624–630 (2011).
  • Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 54, 192–201 (2006).
  • Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28, 639–650 (2008).
  • Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Invest. 118, 3420–3430 (2008).
  • Evans JG, Chavez-Rueda KA, Eddaoudi A et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. J. Immunol. 178, 7868–7878 (2007).
  • Watanabe R, Ishiura N, Nakashima H et al. Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J. Immunol. 184, 4801–4809 (2010).
  • Iwata Y, Matsushita T, Horikawa M et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117, 530–541 (2011).
  • Chujo S, Shirasaki F, Kondo-Miyazaki M, Ikawa Y, Takehara K. Role of connective tissue growth factor and its interaction with basic fibroblast growth factor and macrophage chemoattractant protein-1 in skin fibrosis. J. Cell Physiol. 220, 189–195 (2009).
  • Ferreira AM, Takagawa S, Fresco R, Zhu X, Varga J, DiPietro LA. Diminished induction of skin fibrosis in mice with MCP-1 deficiency. J. Invest. Dermatol. 126, 1900–1908 (2006).
  • Agarwal SK, Wu M, Livingston CK et al. Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts. Arthritis Res. Ther. 13, R3 (2011).
  • Bhattacharyya S, Kelley K, Melichian DS et al. Toll-like receptor 4 signaling augments transforming growth factor-beta responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am. J. Pathol. 182, 192–205 (2013).
  • Batteux, F, Kavian, N, and Servettaz, A. New insights on chemically induced animal models of systemic sclerosis. Curr. Opin. Rheumatol. 23, 511–518 (2011).
  • Yoshizaki A, Yanaba K, Ogawa A et al. The specific free radical scavenger edaravone suppresses fibrosis in the bleomycin-induced and tight skin mouse models of systemic sclerosis. Arthritis Rheum. 63, 3086–3097 (2011).
  • Ghosh AK, Bhattacharyya S, Lakos G, Chen SJ, Mori Y, Varga J. Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma. Arthritis Rheum. 50, 1305–1318 (2004).
  • Wu M, Melichian DS, Chang E, Warner-Blankenship M, Ghosh AK, Varga J. Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma. Am. J. Pathol. 174, 519–533 (2009).
  • Kapoor M, McCann M, Liu S et al. Loss of peroxisome proliferator-activated receptor gamma in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis. Arthritis Rheum. 60, 2822–2829 (2009).
  • Tanaka SS, Kojima Y, Yamaguchi YL, Nishinakamura R, Tam, PP. Impact of WNT signaling on tissue lineage differentiation in the early mouse embryo. Dev. Growth Differ. 53, 843–856 (2011).
  • Cadigan KM, Liu YI. Wnt signaling: complexity at the surface. J. Cell Sci. 119, 395–402 (2006).
  • Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: from flies to human disease. J. Invest. Dermatol. 129, 1614–1627 (2009).
  • Bowley, E, O'Gorman, D.B, and Gan, B.S. Beta-catenin signaling in fibroproliferative disease. J. Surg. Res. 138, 141–150 (2007).
  • 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. 130, 1514–1523 (2010).
  • Wei J, Melichian D, Komura K et al. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum. 63, 1707–1717 (2011).
  • Lam AP, Flozak AS, Russell S et al. Nuclear beta-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am. J. Respir. Cell Mol. Biol. 45, 915–922 (2011).
  • Akhmetshina A, Palumbo K, Dees C et al. Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat. Commun. 3, 735 (2012).
  • Beyer C, Reichert H, Akan H et al. Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis. Ann. Rheum. Dis. 72(7), 1255–1258 (2013).
  • Bergmann C, Akhmetshina A, Dees C et al. Inhibition of glycogen synthase kinase 3beta induces dermal fibrosis by activation of the canonical Wnt pathway. Ann. Rheum. Dis. 70, 2191–2198 (2011).
  • Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes. Dev. 15, 3059–3087 (2001).
  • Dahmane N, Lee J, Robins P, Heller P, Ruiz I, Altaba, A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389, 876–881 (1997).
  • Horn A, Palumbo K, Cordazzo C et al. Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum. 64, 2724–2733 (2012).
  • Zerr P, Palumbo-Zerr K, Distler A et al. Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood 120, 2909–2917 (2012).
  • Brzoska T, Luger TA, Maaser C, Abels C, Bohm M. Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocr. Rev. 29, 581–602 (2008).
  • Colombo G, Buffa R, Bardella MT et al. Anti-inflammatory effects of alpha-melanocyte-stimulating hormone in celiac intestinal mucosa. Neuroimmunomodulation 10, 208–216 (2002).
  • Bohm M, Raghunath M, Sunderkotter C et al. Collagen metabolism is a novel target of the neuropeptide alpha-melanocyte-stimulating hormone. J. Biol. Chem. 279, 6959–6966 (2004).
  • Kokot A, Sindrilaru A, Schiller M et al. alpha-melanocyte-stimulating hormone suppresses bleomycin-induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma: melanocortin peptides as a novel treatment strategy for scleroderma? Arthritis Rheum. 60, 592–603 (2009).

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