Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology that is characterized by fibrosis of the skin and several internal organs, vasculopathy, inflammation and autoimmunity. Animal models have improved our understanding of the pathogenesis of SSc. Many inducible and genetic animal models of SSc have been developed and characterized in the last years. All of these models have different strengths and limitations and mimic different aspects of the pathogenesis of SSc. The purpose of this review is to summarize the characteristics of the various animal models of SSc and to provide an outline of how to use these models to study certain aspects in the pathogenesis of SSc and to test the effects of potential therapeutic approaches.
ElhaiMMeuneCAvouacJKahanAAllanoreYTrends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies.Rheumatology (Oxford)2012;51:(6)1017-1026
2.
KahalehMBShererGKLeRoyECEndothelial injury in scleroderma.J Exp Med1979;149:(6)1326-1335
3.
DeesCSchlottmannIFunkeRet al.The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis.Ann Rheum Dis2014;73:(6)1232-1239
4.
MaurerBStanczykJJüngelAet al.MicroRNA-29, a key regulator of collagen expression in systemic sclerosis.Arthritis Rheum2010;62:(6)1733-1743
5.
TrojanowskaMCellular and molecular aspects of vascular dysfunction in systemic sclerosis.Nat Rev Rheumatol2010;6:(8)453-460
6.
UmezawaHChemistry and mechanism of action of bleomycin.Fed Proc1974;33:(11)2296-2302
7.
LaskyJAOrtizLATonthatBet al.Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis.Am J Physiol1998;2752 Pt 1L365-L371
8.
FildermanAELazoJSMurine strain differences in pulmonary bleomycin metabolism.Biochem Pharmacol1991;42:(1)195-198
9.
SchrierDJKunkelRGPhanSHThe role of strain variation in murine bleomycin-induced pulmonary fibrosis.Am Rev Respir Dis1983;127:(1)63-66
10.
RuzehajiNAvouacJElhaiMet al.Combined effect of genetic background and gender in a mouse model of bleomycin-induced skin fibrosis.Arthritis Res Ther2015;17:(1)145
11.
GabazzaECTaguchiOAdachiYBleomycin-induced lung fibrosis: the authors should have used another method to induce pulmonary lesions resembling human idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2002;165:(6)845-846author reply 846.
AdamsonYIBowdenDHPulmonary injury and repair.Organ culture studies of murine lung after oxygen. Arch Pathol Lab Med1976;100:(12)640-643
14.
TagerAMLaCameraPSheaBSet al.The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak.Nat Med2008;14:(1)45-54
15.
NakashimaTYokoyamaAOnariYet al.Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis.J Allergy Clin Immunol2008;121:(5)1269-1276
16.
DistlerAZiemerCBeyerCet al.Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling.Ann Rheum Dis2014;73:(3)624-627
17.
BergmannCAkhmetshinaADeesCet al.Inhibition of glycogen synthase kinase 3β induces dermal fibrosis by activation of the canonical Wnt pathway.Ann Rheum Dis2011;70:(12)2191-2198
18.
DistlerADelochLHuangJet al.Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling.Ann Rheum Dis2013;72:(9)1575-1580
19.
ChuaFGauldieJLaurentGJPulmonary fibrosis: searching for model answers.Am J Respir Cell Mol Biol2005;33:(1)9-13
20.
MoellerAAskKWarburtonDGauldieJKolbMThe bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?Int J Biochem Cell Biol2008;40:(3)362-382
21.
YamamotoTKurodaMNishiokaKAnimal model of sclerotic skin.III: Histopathological comparison of bleomycin-induced scleroderma in various mice strains. Arch Dermatol Res2000292:(11)535-541
22.
SamboPBaroniSSLuchettiMet 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 Rheum2001;44:(11)2653-2664
23.
SamboPJanninoLCandelaMet al.Monocytes of patients wiht systemic sclerosis (scleroderma spontaneously release in vitro increased amounts of superoxide anion.J Invest Dermatol1999;112:(1)78-84
24.
KavianNServettazAMongaretCet al.Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model.Arthritis Rheum2010;62:(11)3477-3487
25.
ServettazAGoulvestreCKavianNet al.Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse.J Immunol2009;182:(9)5855-5864
26.
VogelsangGBLeeLBensen-KennedyDMPathogenesis and treatment of graft-versus-host disease after bone marrow transplant.Annu Rev Med2003;54:(1)29-52
27.
LambertNCLoYMEricksonTDet al.Male microchimerism in healthy women and women with scleroderma: cells or circulating DNA? A quantitative answer.Blood2002;100:(8)2845-2851
28.
ZerrPDistlerAPalumbo-ZerrKet al.Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease.Am J Pathol2012;181:(5)1672-1680
29.
ZerrPPalumbo-ZerrKDistlerAet al.Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease.Blood2012;120:(14)2909-2917
30.
AndersonBEMcNiffJMJainDBlazarBRShlomchikWDShlomchikMJDistinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ.Blood2005;105:(5)2227-2234
31.
KuwanaMKaburakiJMimoriTKawakamiYTojoTLongitudinal analysis of autoantibody response to topoisomerase I in systemic sclerosis.Arthritis Rheum2000;43:(5)1074-1084
32.
WeinerESEarnshawWCSenécalJLBordwellBJohnsonPRothfieldNFClinical associations of anticentromere antibodies and antibodies to topoisomerase I.A study of 355 patients. Arthritis Rheum1988;31:(3)378-385
33.
YoshizakiAYanabaKOgawaAAsanoYKadonoTSatoSImmunization with DNA topoisomerase I and Freunds complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling.Arthritis Rheum2011;63:(11)3575-3585
34.
SiracusaLDMcGrathRMaQet al.A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.Genome Res1996;6:(4)300-313
35.
GreenMCSweetHOBunkerLETight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton.Am J Pathol1976;82:(3)493-512
36.
MentonDNHessRAThe ultrastructure of collagen in the dermis of tight-skin (Tsk) mutant mice.J Invest Dermatol1980;74:(3)139-147
37.
MentonDNHessRALichtensteinJREisenAThe structure and tensile properties of the skin of tight-skin (Tsk) mutant mice.J Invest Dermatol1978;70:(1)4-10
38.
BaxterRMCrowellTPMcCrannMEFrewEMGardnerHAnalysis of the tight skin (Tsk1/+) mouse as a model for testing antifibrotic agents.Laboratory investigation; a journal of technical methods and pathology. Lab Invest2005;85:(10)1199-1209
39.
BocchieriMHJimenezSAAnimal models of fibrosis.Rheum Dis Clin North Am1990;16:(1)153-167
40.
AvouacJPalumboKTomcikMet al.Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis.Arthritis Rheum2012;64:(5)1642-1652
BayleJFitchJJacobsenKKumarRLafyatisRLemaireRIncreased expression of Wnt2 and SFRP4 in Tsk mouse skin: role of Wnt signaling in altered dermal fibrillin deposition and systemic sclerosis.J Invest Dermatol2008;128:(4)871-881
43.
LemaireRFarinaGBayleJet al.Antagonistic effect of the matricellular signaling protein CCN3 on TGF-beta- and Wnt-mediated fibrillinogenesis in systemic sclerosis and Marfan syndrome.J Invest Dermatol2010;130:(6)1514-1523
44.
KomuraKFujimotoMYanabaKet al.Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse.Ann Rheum Dis2008;67:(6)867-872
45.
MuraiCSaitoSKasturiKNBonaCASpontaneous occurrence of anti-fibrillin-1 autoantibodies in tight-skin mice.Autoimmunity1998;28:(3)151-155
46.
PhelpsRGDaianCShibataSFleischmajerRBonaCAInduction of skin fibrosis and autoantibodies by infusion of immunocompetent cells from tight skin mice into C57BL/6 Pa/Pa mice.J Autoimmun1993;6:(6)701-718
47.
BocchieriMHHenriksenPDKasturiKNMuryoiTBonaCAJimenezSAEvidence for autoimmunity in the tight skin mouse model of systemic sclerosis.Arthritis Rheum1991;34:(5)599-605
48.
HatakeyamaAKasturiKNWolfIPhelpsRGBonaCACorrelation between the concentration of serum anti-topoisomerase I autoantibodies and histological and biochemical alterations in the skin of tight skin mice.Cell Immunol1996167:(1)135-140
49.
BorosPChenJMBonaCUnkelessJCAutoimmune mice make anti-Fc gamma receptor antibodies.J Exp Med1990;171:(5)1581-1595
50.
ShibataSMuryoiTSaitohYBrumeanuTDBonaCAKasturiKNImmunochemical and molecular characterization of anti-RNA polymerase I autoantibodies produced by tight skin mouse.J Clin Invest1993;92:(2)984-992
51.
ChristnerPJPetersJHawkinsDSiracusaLDJiménezSAThe tight skin 2 mouse.An animal model of scleroderma displaying cutaneous fibrosis and mononuclear cell infiltration. Arthritis Rheum1995;38:(12)1791-1798
52.
LongKBLiZBurgwinCMet al.The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene.J Invest Dermatol2015;135:(3)718-727
53.
ChristnerPJHitrayaEGPetersJMcGrathRJiménezSATranscriptional activation of the alpha1(I) procollagen gene and up-regulation of alpha1(I) and alpha1(III) procollagen messenger RNA in dermal fibroblasts from tight skin 2 mice.Arthritis Rheum1998;41:(12)2132-2142
54.
GentilettiJMcCloskeyLJArtlettCMPetersJJimenezSAChristnerPJDemonstration of autoimmunity in the tight skin-2 mouse: a model for scleroderma.J Immunol2005;175:(4)2418-2426
55.
AsanoYSatoSAnimal models of scleroderma: current state and recent development.Curr Rheumatol Rep201315:(12)382
56.
KuboMCzuwara-LadykowskaJMoussaOet al.Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin.Am J Pathol2003;163:(2)571-581
57.
TaniguchiTAsanoYAkamataKet al.Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated Fli-1-haploinsufficient mice.Arthritis Rheum (Munch)2015;67:(2)517-526
58.
AsanoYStawskiLHantFet al.Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy.Am J Pathol2010;176:(4)1983-1998
59.
DongJTChenCEssential role of KLF5 transcription factor in cell proliferation and differentiation and its implications for human diseases.Cell Mol Life Sci2009;66:(16)2691-2706
60.
TakedaNManabeIUchinoYet al.Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload.J Clin Invest2010;120:(1)254-265
61.
FujiuKManabeINagaiRRenal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice.J Clin Invest2011;121:(9)3425-3441
62.
WhitfieldMLFinlayDRMurrayJIet al.Systemic and cell type-specific gene expression patterns in scleroderma skin.Proc Natl Acad Sci USA2003;100:(21)12319-12324
63.
NodaSAsanoYNishimuraSet al.Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis.Nat Commun2014;55797
64.
AsanoYRecent advances in animal models of systemic sclerosis.J Dermatol2016;43:(1)19-28
65.
EferlRHasselblattPRathMet al.Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1.Proc Natl Acad Sci USA2008;105:(30)10525-10530
66.
MaurerBBuschNJüngelAet al.Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis.Circulation2009;120:(23)2367-2376
67.
MaurerBReichNJuengelAet al.Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis.Ann Rheum Dis2012;71:(8)1382-1387
68.
ReichNMaurerBAkhmetshinaAet al.The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis.Arthritis Rheum2010;62:(1)280-290
69.
DeesCZerrPTomcikMet al.Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis.Arthritis Rheum2011;63:(5)1396-1404
70.
VenalisPKumánovicsGSchulze-KoopsHet al.Cardiomyopathy in murine models of systemic sclerosis.Arthritis Rheum (Munch)2015;67:(2)508-516
71.
Gomez-ArroyoJSaleemSJMizunoSet al.A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects.Am J Physiol Lung Cell Mol Physiol2012302:(10)L977-L991
72.
DrabMVerkadePElgerMet al.Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice.Science2001;293:(5539)2449-2452
73.
ZhaoYYLiuYStanRVet al.Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice.Proc Natl Acad Sci USA2002;99:(17)11375-11380
74.
WangXMZhangYKimHPet al.Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis.J Exp Med2006;203:(13)2895-2906
75.
WunderlichCSchoberKLangeSAet al.Disruption of caveolin-1 leads to enhanced nitrosative stress and severe systolic and diastolic heart failure.Biochem Biophys Res Commun2006;340:(2)702-708
76.
MurataTLinMIHuangYet al.Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout mice.J Exp Med2007;204:(10)2373-2382
77.
CohenAWParkDSWoodmanSEet al.Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts.Am J Physiol Cell Physiol2003;284:(2)C457-C474
78.
MondinoAResnatiMBlasiFStructure and function of the urokinase receptor.Thromb Haemost1999;82Suppl 119-22
79.
RagnoPThe urokinase receptor: a ligand or a receptor? Story of a sociable molecule.Cell Mol Life Sci2006;63:(9)1028-1037
80.
DAlessioSFibbiGCinelliMet al.Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis.Arthritis Rheum2004;50:(10)3275-3285
81.
MargheriFManettiMSerratìSet al.Domain 1 of the urokinase-type plasminogen activator receptor is required for its morphologic and functional, beta2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: failure of association in systemic sclerosis endothelial cells.Arthritis Rheum2006;54:(12)3926-3938
82.
ManettiMRosaIMiliaAFet al.Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma?Ann Rheum Dis2014;73:(9)1700-1709
83.
GershwinMEAbplanalpHCastlesJJet al.Characterization of a spontaneous disease of white leghorn chickens resembling progressive systemic sclerosis (scleroderma).J Exp Med1981;153:(6)1640-1659
84.
NguyenVASgoncRDietrichHWickGEndothelial injury in internal organs of University of California at Davis line 200 (UCD 200) chickens, an animal model for systemic sclerosis (Scleroderma).J Autoimmun2000;14:(2)143-149
85.
SgoncRGruschwitzMSDietrichHRecheisHGershwinMEWickGEndothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma.J Clin Invest1996;98:(3)785-792
86.
WickGAnderssonLHalaKet al.Avian models with spontaneous autoimmune diseases.Adv Immunol2006;9271-117
LafyatisRTransforming growth factor βat the centre of systemic sclerosis.Nat Rev Rheumatol2014;10:(12)706-719
89.
WynnTACellular and molecular mechanisms of fibrosis.J Pathol2008;214:(2)199-210
90.
SonnylalSDentonCPZhengBet al.Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma.Arthritis Rheum2007;56:(1)334-344
91.
AkhmetshinaAPalumboKDeesCet al.Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis.Nat Commun2012;3735.
92.
BeyerCZenzmaierCPalumbo-ZerrKet al.Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling.Ann Rheum Dis2015;74:(7)1408-1416
ZhangYDeesCBeyerCet al.Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis.Ann Rheum Dis2015;74:(5)936-943
95.
DentonCPZhengBEvansLAet 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 Chem2003;278:(27)25109-25119
96.
DentonCPLindahlGEKhanKet al.Activation of key profibrotic mechanisms in transgenic fibroblasts expressing kinase-deficient type II Transforming growth factor-beta receptor (TbetaRIIdeltak).J Biol Chem2005;280:(16)16053-16065
97.
Derrett-SmithECDooleyAKhanKShi-wenXAbrahamDDentonCPSystemic vasculopathy with altered vasoreactivity in a transgenic mouse model of scleroderma.Arthritis Res Ther2010;12:(2)R69
98.
BorkPThe modular architecture of a new family of growth regulators related to connective tissue growth factor.FEBS Lett1993;327:(2)125-130
99.
LeaskAAbrahamDJAll in the CCN family: essential matricellular signaling modulators emerge from the bunker.J Cell Sci2006;119Pt 234803-4810
100.
FriedrichsenSHeuerHChristSet al.CTGF expression during mouse embryonic development.Cell Tissue Res2003;312:(2)175-188
101.
SonnylalSShi-WenXLeoniPet al.Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis.Arthritis Rheum2010;62:(5)1523-1532
BeyerCSchrammAAkhmetshinaAet al.β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis.Ann Rheum Dis2012;71:(5)761-767
104.
HendersonWRJrChiEYYeXet al.Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis.Proc Natl Acad Sci USA2010;107:(32)14309-14314
105.
WeiJMelichianDKomuraKet al.Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma?Arthritis Rheum2011;63:(6)1707-1717
106.
HamburgEJAtitRPSustained β-catenin activity in dermal fibroblasts is sufficient for skin fibrosis.J Invest Dermatol2012132:(10)2469-2472
107.
Hamburg-ShieldsEDiNuoscioGJMullinNKLafyatisRAtitRPSustained β-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes.J Pathol2015;235:(5)686-697
