Skip to main content
Erschienen in: Archives of Dermatological Research 1/2013

01.01.2013 | Review Article

Morphogen pathways as molecular targets for the treatment of fibrosis in systemic sclerosis

verfasst von: Christian Beyer, Clara Dees, Jörg H. W. Distler

Erschienen in: Archives of Dermatological Research | Ausgabe 1/2013

Einloggen, um Zugang zu erhalten

Abstract

Wnt-, Hedgehog- and Notch-signaling cascades are morphogen pathways that play crucial roles in development and tissue homeostasis. While morphogen pathways are tightly regulated at multiple levels, inappropriate activation of Wnt, Hedgehog and Notch signaling has been implicated into the pathogenesis of various diseases. In particular, Wnt, Hedgehog and Notch signaling have emerged as central players in the pathogenesis of fibrotic diseases. Here, we will review the pro-fibrotic effects of Wnt, Hedgehog and Notch signaling in systemic sclerosis (SSc), prototypical systemic fibrotic disease. Wnt, Hedgehog and Notch pathways are activated in SSc. They potently stimulate fibroblasts to differentiate into myofibroblasts and to release collagen and other extracellular matrix components. Genetic or pharmacological inhibition of morphogen pathways effectively prevents experimental fibrosis in different preclinical models and induces regression of pre-established fibrosis. As several inhibitors of Wnt, Hedgehog and Notch have recently been developed with first ones being already approved for clinical trials, morphogen pathways maybe a novel approach for the treatment of fibrosis.
Literatur
1.
Zurück zum Zitat Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, Schneider H, Sadowski A, Riener MO, MacDougald OA, Distler O, Schett G, Distler JH (2012) Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun 3:735PubMedCrossRef Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, Schneider H, Sadowski A, Riener MO, MacDougald OA, Distler O, Schett G, Distler JH (2012) Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun 3:735PubMedCrossRef
2.
Zurück zum Zitat Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138(17):3593–3612PubMedCrossRef Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138(17):3593–3612PubMedCrossRef
3.
Zurück zum Zitat Bayle J, Fitch J, Jacobsen K, Kumar R, Lafyatis R, Lemaire R (2008) 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 128(4):871–881PubMedCrossRef Bayle J, Fitch J, Jacobsen K, Kumar R, Lafyatis R, Lemaire R (2008) 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 128(4):871–881PubMedCrossRef
4.
Zurück zum Zitat Bergmann C, Akhmetshina A, Dees C, Palumbo K, Zerr P, Beyer C, Zwerina J, Distler O, Schett G, Distler JH (2011) Inhibition of glycogen synthase kinase 3beta induces dermal fibrosis by activation of the canonical Wnt pathway. Ann Rheum Dis 70(12):2191–2198PubMedCrossRef Bergmann C, Akhmetshina A, Dees C, Palumbo K, Zerr P, Beyer C, Zwerina J, Distler O, Schett G, Distler JH (2011) Inhibition of glycogen synthase kinase 3beta induces dermal fibrosis by activation of the canonical Wnt pathway. Ann Rheum Dis 70(12):2191–2198PubMedCrossRef
5.
Zurück zum Zitat Beyer C, Distler JH (2009) The scientific basis for novel treatments of systemic sclerosis. F1000 Med Rep 1 Beyer C, Distler JH (2009) The scientific basis for novel treatments of systemic sclerosis. F1000 Med Rep 1
6.
Zurück zum Zitat Beyer C, Distler O, Distler JH (2012) Innovative antifibrotic therapies in systemic sclerosis. Curr Opin Rheumatol 24(3):274–280PubMedCrossRef Beyer C, Distler O, Distler JH (2012) Innovative antifibrotic therapies in systemic sclerosis. Curr Opin Rheumatol 24(3):274–280PubMedCrossRef
7.
Zurück zum Zitat Beyer C, Schramm A, Akan H, Dees C, Lin N-Y, Distler A, Gelse K, Varga J, Distler O, Schett G, Distler JH (2012) Blockade of canonical Wnt signaling inhibits experimental dermal fibrosis. Ann Rheum Dis (submitted) Beyer C, Schramm A, Akan H, Dees C, Lin N-Y, Distler A, Gelse K, Varga J, Distler O, Schett G, Distler JH (2012) Blockade of canonical Wnt signaling inhibits experimental dermal fibrosis. Ann Rheum Dis (submitted)
8.
Zurück zum Zitat Beyer C, Schramm A, Akhmetshina A, Dees C, Kireva T, Gelse K, Sonnylal S, de Crombrugghe B, Taketo MM, Distler O, Schett G, Distler JH (2012) Beta-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis 71(5):761–767PubMedCrossRef Beyer C, Schramm A, Akhmetshina A, Dees C, Kireva T, Gelse K, Sonnylal S, de Crombrugghe B, Taketo MM, Distler O, Schett G, Distler JH (2012) Beta-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis 71(5):761–767PubMedCrossRef
9.
Zurück zum Zitat Canettieri G, Di Marcotullio L, Greco A, Coni S, Antonucci L, Infante P, Pietrosanti L, De Smaele E, Ferretti E, Miele E, Pelloni M, De Simone G, Pedone EM, Gallinari P, Giorgi A, Steinkuhler C, Vitagliano L, Pedone C, Schinin ME, Screpanti I, Gulino A (2010) Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol 12(2):132–142PubMedCrossRef Canettieri G, Di Marcotullio L, Greco A, Coni S, Antonucci L, Infante P, Pietrosanti L, De Smaele E, Ferretti E, Miele E, Pelloni M, De Simone G, Pedone EM, Gallinari P, Giorgi A, Steinkuhler C, Vitagliano L, Pedone C, Schinin ME, Screpanti I, Gulino A (2010) Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol 12(2):132–142PubMedCrossRef
10.
Zurück zum Zitat Cheng SY, Bishop JM (2002) Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA 99(8):5442–5447PubMedCrossRef Cheng SY, Bishop JM (2002) Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA 99(8):5442–5447PubMedCrossRef
11.
Zurück zum Zitat Cox B, Briscoe J, Ulloa F (2010) SUMOylation by Pias1 regulates the activity of the Hedgehog dependent Gli transcription factors. PLoS One 5(8):e11996PubMedCrossRef Cox B, Briscoe J, Ulloa F (2010) SUMOylation by Pias1 regulates the activity of the Hedgehog dependent Gli transcription factors. PLoS One 5(8):e11996PubMedCrossRef
12.
Zurück zum Zitat D’Souza B, Meloty-Kapella L, Weinmaster G (2010) Canonical and non-canonical Notch ligands. Curr Top Dev Biol 92:73–129PubMedCrossRef D’Souza B, Meloty-Kapella L, Weinmaster G (2010) Canonical and non-canonical Notch ligands. Curr Top Dev Biol 92:73–129PubMedCrossRef
13.
Zurück zum Zitat Dees C, Tomcik M, Zerr P, Akhmetshina A, Horn A, Palumbo K, Beyer C, Zwerina J, Distler O, Schett G, Distler JH (2011) Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis 70(7):1304–1310PubMedCrossRef Dees C, Tomcik M, Zerr P, Akhmetshina A, Horn A, Palumbo K, Beyer C, Zwerina J, Distler O, Schett G, Distler JH (2011) Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis 70(7):1304–1310PubMedCrossRef
14.
Zurück zum Zitat Dees C, Zerr P, Tomcik M, Beyer C, Horn A, Akhmetshina A, Palumbo K, Reich N, Zwerina J, Sticherling M, Mattson MP, Distler O, Schett G, Distler JH (2011) Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum 63(5):1396–1404PubMedCrossRef Dees C, Zerr P, Tomcik M, Beyer C, Horn A, Akhmetshina A, Palumbo K, Reich N, Zwerina J, Sticherling M, Mattson MP, Distler O, Schett G, Distler JH (2011) Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum 63(5):1396–1404PubMedCrossRef
15.
Zurück zum Zitat Distler A, Deloch L, Huang J, Dees C, Lin NY, Beyer C, Distler O, Schett G, Distler JH (2011) Inactivation of tankyrases inhibits canonical Wnt signaling and reduces experimental fibrosis. Ann Rheum Dis (submitted) Distler A, Deloch L, Huang J, Dees C, Lin NY, Beyer C, Distler O, Schett G, Distler JH (2011) Inactivation of tankyrases inhibits canonical Wnt signaling and reduces experimental fibrosis. Ann Rheum Dis (submitted)
16.
Zurück zum Zitat Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16(5):633–647PubMedCrossRef Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16(5):633–647PubMedCrossRef
17.
18.
Zurück zum Zitat Gallet A (2011) Hedgehog morphogen: from secretion to reception. Trends Cell Biol 21(4):238–246PubMedCrossRef Gallet A (2011) Hedgehog morphogen: from secretion to reception. Trends Cell Biol 21(4):238–246PubMedCrossRef
19.
Zurück zum Zitat Geffers I, Serth K, Chapman G, Jaekel R, Schuster-Gossler K, Cordes R, Sparrow DB, Kremmer E, Dunwoodie SL, Klein T, Gossler A (2007) Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo. J Cell Biol 178(3):465–476PubMedCrossRef Geffers I, Serth K, Chapman G, Jaekel R, Schuster-Gossler K, Cordes R, Sparrow DB, Kremmer E, Dunwoodie SL, Klein T, Gossler A (2007) Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo. J Cell Biol 178(3):465–476PubMedCrossRef
20.
Zurück zum Zitat Groth C, Fortini ME (2012) Therapeutic approaches to modulating Notch signaling: current challenges and future prospects. Semin Cell Dev Biol 23(4):465–472PubMedCrossRef Groth C, Fortini ME (2012) Therapeutic approaches to modulating Notch signaling: current challenges and future prospects. Semin Cell Dev Biol 23(4):465–472PubMedCrossRef
21.
Zurück zum Zitat He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 20(4):765–776PubMedCrossRef He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 20(4):765–776PubMedCrossRef
22.
Zurück zum Zitat Horn A, Kireva T, Palumbo-Zerr K, Dees C, Tomcik M, Cordazzo C, Zerr P, Akhmetshina A, Ruat M, Distler O, Beyer C, Schett G, Distler JH (2012) Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann Rheum Dis 71(5):785–789PubMedCrossRef Horn A, Kireva T, Palumbo-Zerr K, Dees C, Tomcik M, Cordazzo C, Zerr P, Akhmetshina A, Ruat M, Distler O, Beyer C, Schett G, Distler JH (2012) Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann Rheum Dis 71(5):785–789PubMedCrossRef
23.
Zurück zum Zitat Horn A, Palumbo K, Cordazzo C, Dees C, Akhmetshina A, Tomcik M, Zerr P, Avouac J, Gusinde J, Zwerina J, Roudaut H, Traiffort E, Ruat M, Distler O, Schett G, Distler JH (2012) Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum. doi:10.1002/art.34444 Horn A, Palumbo K, Cordazzo C, Dees C, Akhmetshina A, Tomcik M, Zerr P, Avouac J, Gusinde J, Zwerina J, Roudaut H, Traiffort E, Ruat M, Distler O, Schett G, Distler JH (2012) Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum. doi:10.​1002/​art.​34444
24.
Zurück zum Zitat Hui CC, Angers S (2011) Gli proteins in development and disease. Annu Rev Cell Dev Biol 27:513–537PubMedCrossRef Hui CC, Angers S (2011) Gli proteins in development and disease. Annu Rev Cell Dev Biol 27:513–537PubMedCrossRef
25.
Zurück zum Zitat Imbimbo BP, Giardina GA (2011) Gamma-secretase inhibitors and modulators for the treatment of Alzheimer’s disease: disappointments and hopes. Curr Top Med Chem 11(12):1555–1570PubMedCrossRef Imbimbo BP, Giardina GA (2011) Gamma-secretase inhibitors and modulators for the treatment of Alzheimer’s disease: disappointments and hopes. Curr Top Med Chem 11(12):1555–1570PubMedCrossRef
26.
Zurück zum Zitat Ingham PW, Nakano Y, Seger C (2011) Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet 12(6):393–406PubMedCrossRef Ingham PW, Nakano Y, Seger C (2011) Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet 12(6):393–406PubMedCrossRef
27.
Zurück zum Zitat Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D, Klekota J, Tamayo P, Nguyen PT, Tolstorukov M, Park PJ, Cho YJ, Hsiao K, Buonamici S, Pomeroy SL, Mesirov JP, Ruffner H, Bouwmeester T, Luchansky SJ, Murtie J, Kelleher JF, Warmuth M, Sellers WR, Roberts CW, Dorsch M (2010) Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med 16(12):1429–1433PubMedCrossRef Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D, Klekota J, Tamayo P, Nguyen PT, Tolstorukov M, Park PJ, Cho YJ, Hsiao K, Buonamici S, Pomeroy SL, Mesirov JP, Ruffner H, Bouwmeester T, Luchansky SJ, Murtie J, Kelleher JF, Warmuth M, Sellers WR, Roberts CW, Dorsch M (2010) Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med 16(12):1429–1433PubMedCrossRef
28.
Zurück zum Zitat Kavian N, Servettaz A, Mongaret C, Wang A, Nicco C, Chereau C, Grange P, Vuiblet V, Birembaut P, Diebold MD, Weill B, Dupin N, Batteux F (2010) Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum 62(11):3477–3487PubMedCrossRef Kavian N, Servettaz A, Mongaret C, Wang A, Nicco C, Chereau C, Grange P, Vuiblet V, Birembaut P, Diebold MD, Weill B, Dupin N, Batteux F (2010) Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum 62(11):3477–3487PubMedCrossRef
29.
Zurück zum Zitat Kikuchi A, Yamamoto H, Sato A (2009) Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol 19(3):119–129PubMedCrossRef Kikuchi A, Yamamoto H, Sato A (2009) Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol 19(3):119–129PubMedCrossRef
30.
Zurück zum Zitat Kobayashi K, Luo M, Zhang Y, Wilkes DC, Ge G, Grieskamp T, Yamada C, Liu TC, Huang G, Basson CT, Kispert A, Greenspan DS, Sato TN (2009) Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nat Cell Biol 11(1):46–55PubMedCrossRef Kobayashi K, Luo M, Zhang Y, Wilkes DC, Ge G, Grieskamp T, Yamada C, Liu TC, Huang G, Basson CT, Kispert A, Greenspan DS, Sato TN (2009) Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nat Cell Biol 11(1):46–55PubMedCrossRef
31.
Zurück zum Zitat Konigshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Gunther A, Eickelberg O (2009) WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 119(4):772–787PubMed Konigshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Gunther A, Eickelberg O (2009) WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 119(4):772–787PubMed
32.
Zurück zum Zitat Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C, Yang LT, Boulter J, Sun YE, Kintner C, Weinmaster G (2005) The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol 170(6):983–992PubMedCrossRef Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C, Yang LT, Boulter J, Sun YE, Kintner C, Weinmaster G (2005) The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol 170(6):983–992PubMedCrossRef
33.
Zurück zum Zitat Lubman OY, Ilagan MX, Kopan R, Barrick D (2007) Quantitative dissection of the Notch: CSL interaction: insights into the Notch-mediated transcriptional switch. J Mol Biol 365(3):577–589PubMedCrossRef Lubman OY, Ilagan MX, Kopan R, Barrick D (2007) Quantitative dissection of the Notch: CSL interaction: insights into the Notch-mediated transcriptional switch. J Mol Biol 365(3):577–589PubMedCrossRef
34.
Zurück zum Zitat MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26PubMedCrossRef MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26PubMedCrossRef
36.
Zurück zum Zitat Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 31(12):2670–2684PubMedCrossRef Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 31(12):2670–2684PubMedCrossRef
38.
Zurück zum Zitat Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 278(46):46107–46116PubMedCrossRef Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 278(46):46107–46116PubMedCrossRef
39.
Zurück zum Zitat Simons BD, Clevers H (2011) Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145(6):851–862PubMedCrossRef Simons BD, Clevers H (2011) Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145(6):851–862PubMedCrossRef
40.
Zurück zum Zitat Sirin Y, Susztak K (2012) Notch in the kidney: development and disease. J Pathol 226(2):394–403PubMedCrossRef Sirin Y, Susztak K (2012) Notch in the kidney: development and disease. J Pathol 226(2):394–403PubMedCrossRef
41.
Zurück zum Zitat Steen VD, Medsger TA (2007) Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 66(7):940–944PubMedCrossRef Steen VD, Medsger TA (2007) Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 66(7):940–944PubMedCrossRef
42.
Zurück zum Zitat Valenta T, Hausmann G, Basler K (2012) The many faces and functions of beta-catenin. EMBO J 31(12):2714–2736PubMedCrossRef Valenta T, Hausmann G, Basler K (2012) The many faces and functions of beta-catenin. EMBO J 31(12):2714–2736PubMedCrossRef
43.
Zurück zum Zitat van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435(7044):959–963PubMedCrossRef van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435(7044):959–963PubMedCrossRef
44.
Zurück zum Zitat Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117(3):557–567PubMedCrossRef Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117(3):557–567PubMedCrossRef
45.
Zurück zum Zitat Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, Gottardi CJ, Atit R, Whitfield ML, Varga J (2012) Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum. doi:10.1002/art.34424 PubMed Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, Gottardi CJ, Atit R, Whitfield ML, Varga J (2012) Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum. doi:10.​1002/​art.​34424 PubMed
46.
Zurück zum Zitat Wei J, Melichian D, Komura K, Hinchcliff M, Lam AP, Lafyatis R, Gottardi CJ, MacDougald OA, Varga J (2011) Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum 63(6):1707–1717PubMedCrossRef Wei J, Melichian D, Komura K, Hinchcliff M, Lam AP, Lafyatis R, Gottardi CJ, MacDougald OA, Varga J (2011) Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum 63(6):1707–1717PubMedCrossRef
47.
Zurück zum Zitat Zerr P, Palumbo-Zerr K, Distler A, Tomcik M, Vollath S, Munoz LE, Beyer C, Dees C, Egberts F, Tinazzi I, Del Galdo F, Distler O, Schett G, Spriewald BM, Distler JH (2012) Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood. doi:10.1182/blood-2012-01-403428 Zerr P, Palumbo-Zerr K, Distler A, Tomcik M, Vollath S, Munoz LE, Beyer C, Dees C, Egberts F, Tinazzi I, Del Galdo F, Distler O, Schett G, Spriewald BM, Distler JH (2012) Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood. doi:10.​1182/​blood-2012-01-403428
48.
Zurück zum Zitat Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD (2000) SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC to facilitate NotchIC function. Mol Cell Biol 20(7):2400–2410PubMedCrossRef Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD (2000) SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC to facilitate NotchIC function. Mol Cell Biol 20(7):2400–2410PubMedCrossRef
49.
Zurück zum Zitat Liu Z, Lu CL, Cui LP, Hu YL, Yu Q, Jiang Y, Ma T, Jiao DK, Wang D, Jia CY (2012) MicroRNA-146a modulates TGF-beta1-induced phenotypic differentiation in human dermal fibroblasts by targeting SMAD4. Arch Dermatol Res 304:195–202PubMedCrossRef Liu Z, Lu CL, Cui LP, Hu YL, Yu Q, Jiang Y, Ma T, Jiao DK, Wang D, Jia CY (2012) MicroRNA-146a modulates TGF-beta1-induced phenotypic differentiation in human dermal fibroblasts by targeting SMAD4. Arch Dermatol Res 304:195–202PubMedCrossRef
50.
Zurück zum Zitat Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S (2012) Clinical significance of circulating platelet-activating factor acetylhydrolase levels in systemic sclerosis. Arch Dermatol Res 304:203–208PubMedCrossRef Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S (2012) Clinical significance of circulating platelet-activating factor acetylhydrolase levels in systemic sclerosis. Arch Dermatol Res 304:203–208PubMedCrossRef
51.
Zurück zum Zitat Yanaba K, Asano Y, Noda S, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Tada Y, Sugaya M, Kadono T, Sato S (2012) Increased production of soluble inducible costimulator in patients with diffuse cutaneous systemic sclerosis. Arch Dermatol Res. doi:10.1007/s00403-012-1292-7 Yanaba K, Asano Y, Noda S, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Tada Y, Sugaya M, Kadono T, Sato S (2012) Increased production of soluble inducible costimulator in patients with diffuse cutaneous systemic sclerosis. Arch Dermatol Res. doi:10.​1007/​s00403-012-1292-7
52.
Zurück zum Zitat Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S (2012) A possible contribution of elevated serum clusterin levels to the inhibition of digital ulcers and pulmonary arterial hypertension in systemic sclerosis. Arch Dermatol Res 304:459–463PubMedCrossRef Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S (2012) A possible contribution of elevated serum clusterin levels to the inhibition of digital ulcers and pulmonary arterial hypertension in systemic sclerosis. Arch Dermatol Res 304:459–463PubMedCrossRef
Metadaten
Titel
Morphogen pathways as molecular targets for the treatment of fibrosis in systemic sclerosis
verfasst von
Christian Beyer
Clara Dees
Jörg H. W. Distler
Publikationsdatum
01.01.2013
Verlag
Springer-Verlag
Erschienen in
Archives of Dermatological Research / Ausgabe 1/2013
Print ISSN: 0340-3696
Elektronische ISSN: 1432-069X
DOI
https://doi.org/10.1007/s00403-012-1304-7

Weitere Artikel der Ausgabe 1/2013

Archives of Dermatological Research 1/2013 Zur Ausgabe

Leitlinien kompakt für die Dermatologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Dermatologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.