Animal models of systemic sclerosis: their utility and limitations

Figures & data

Table 1 Prominent features of animal models of systemic sclerosis

	Fibrotic site	Vasculopathy	Inflammation	Autoantibody target
Spontaneous genetic models
Tsk1/+ mouse^Citation5,Citation8,Citation11	Dermis	Cardiomyopathy and abnormal vascular tone	Absent	Fibrillin-1
Tsk2/+ mouse^Citation29,Citation31,Citation32	Dermis	Absent	Modest inflammation	ANA, DNA topoisomerase I/Scl70
UCD-200 chicken^Citation35,Citation37	Skin and organs	Vascular occlusion	Perivascular infiltrate	ssDNA, histones, dsDNA
Inducible models
Bleomycin model^Citation51^–^Citation53	Skin and lung	Present	Peaks between days 3 and 5, then declines	Gastric mucosa
Hypochlorous model^Citation71,Citation73	Skin and lung	Vasculopathy of small renal arteries	Present in the dermis	Higher but not significant levels of DNA topoisomerase I/Scl70
Sclerodermatous GVHD^Citation78	Skin	Present	Inflammation and cytokine perturbations	DNA topoisomerase I/Scl70
Angiotensin II model^Citation79,Citation80	Present	Present, also has cardiovascular remodeling	Perivascular inflammation	Not reported
DNA topoisomerase I and CFA^Citation83	Skin and lung	Not reported	Cytokine perturbations and inflammation peaks at 8 weeks	DNA topoisomerase I/Scl70
Transgenic models
Endothelin-1^Citation87,Citation88	Kidney and lung	Reduced	Present	Not reported
FRA-2^Citation95,Citation96	Skin and lung	Present	Present	Not reported
Type I TGF-β receptor^Citation97	Dermis	Present	Absent	Not reported
Kinase-deficient type II TGF-β receptor^Citation102,Citation104	Dermis and lung	Absent but addition of a VEGFR inhibitor promoted vasculopathy	Not reported	Not reported
PDGFR-α^Citation107	Skin and organs	Not reported	Cytokine perturbations	DNA topoisomerase I/Scl70
Knockout models
Caveolin-1^Citation110,Citation111,Citation180	Dermis	Present	Increased inflammatory responses	Not reported
Egr-1^Citation119	Reduced fibrosis	Not reported	Reduced inflammation	Not reported
Fli1^Citation123	Skin	Present	Not reported	Not reported
MCP-1^Citation124	Reduced fibrosis	Not reported	Reduced inflammation	Not reported
mPGES-1^Citation128	Reduced fibrosis	Not reported	Reduced inflammation	Not reported
PPARγ^Citation131	Dermis	Not reported	Increased inflammation	Not reported
PTEN^Citation136	Dermis	Not reported	Not reported	Not reported
Relaxin^Citation139	Skin	Not reported	Not reported	Not reported

Abbreviations: ANA, antinuclear antibody; CFA, Freund’s complete adjuvant; MCP-1, macrophage chemoattractant protein-1; PPARγ, peroxisome proliferator-activated receptor-gamma; PTEN, phosphatase and tensin homolog; FRA-2, Fos-related antigen-2; Egr-1, early growth response gene; Fli1, Friend leukemia integration factor-1; TGF-β, transforming growth factor-beta; PDGFR, platelet-derived growth factor receptor; ssDNA, single-stranded DNA; dsDNA, double-stranded DNA; VEGFR, vascular endothelial growth factor receptor; GVHD, graft versus host disease; Tsk1/+, tight skin 1; Tsk2/+, tight skin 2; UCD-200, University of California at Davis line 200; mPGES-1, microsomal prostaglandin E2 synthase-1.

Table 2 Preclinical testing of drugs in mice and their outcome in systemic sclerosis

Drug	Mode of action	Efficacy in mice	Efficacy in SSc
Anakinra	IL-1 receptor antagonist	Effectively blocked pulmonary fibrosis in the bleomycin model^Citation143	Currently undergoing clinical trial, but no data are available
Bosentan	Endothelin-1 receptor antagonist	Tested in the Tsk1/+ mouse and shown to effectively reduce moderate vasculopathy^Citation94 and shown to be effective against bleomycin- induced pulmonary fibrosis^Citation181	Drug well tolerated and the data suggest that bosentan may be effective at stabilizing or improving the microcirculation in SSc^Citation166,Citation167
Colchicine	Inhibits mitosis	This drug demonstrated moderate protection against pulmonary fibrosis^Citation153 but was not tested for skin fibrosis	One study reported clinical improvement^Citation182 whereas other studies report no improvement^Citation154,Citation155
Cyclophosphamide	Nitrogen mustard alkylating agent	Use of bleomycin and cyclophosphamide as chemotherapeutic drugs is associated with side effects including toxicity to the respiratory system^Citation176 Their coadministration may enhance lung toxicity which may subsequently progress to the lung fibrosis	One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and health-related quality of life^Citation177
Cyclosporin A	Immunosuppressant	Studies show efficacy at ameliorating bleomycin induced lung fibrosis^Citation144,Citation145	Limited studies in SSc patients; however, patients on cyclosporine appear to do well^Citation146 but not without a significant risk of renal toxicity^Citation147
Etanercept	TNF inhibitor	Effective at reducing bleomycin-induced dermal fibrosis^Citation156	Shown to be useful at treating inflammatory joint diseases in SSc^Citation157 but may not be effective against fibrosis^Citation158 and could be fatal^Citation159
Halofuginone	Inhibits collagen synthesis and Th17 differentiation	Effectively reduced fibrosis in Tsk1/+ mice, and mice with chronic GVHD^Citation165	Five of 12 SSc patients demonstrated efficacy in a small pilot study^Citation165 A larger clinical trial has not been performed
Imatinib	Tyrosine kinase inhibitor	Reduced dermal and hypodermal thickening in the Tsk1/+ mouse and reduced overt fibrosis in the bleomycin mouse model^Citation25	Frequent adverse events with poor tolerability^Citation160
Iloprost	Prostacyclin agonist	Iloprost has a protective effect on bleomycin-induced pulmonary fibrosis^Citation161	Heterogeneous results of small trials make the efficacy of iloprost hard to assess^Citation162,Citation163
Losartan	Angiotensin II receptor antagonist	Losartan had an inhibitory effect on bleomycin-induced pulmonary fibrosis^Citation168,Citation169	Short-term study demonstrated efficacy for treating Raynaud’s phenomenon; however, no studies have been published to suggest it might be effective against fibrosis
Methotrexate	Inhibits folic acid metabolism	No efficacy against bleomycin^Citation175	A recent study suggested that methotrexate did not significantly alter the skin score^Citation173 but seems successful in treating juvenile localized SSc^Citation174
Minocycline	Antibiotic	Not tested	Failed open-label trial^Citation172
Mycophenolate mofetil	Immunosuppressant	Mycophenolate mofetil was able to prevent the development of bleomycin-induced dermal fibrosis^Citation149	In a small study, mycophenolate mofetil demonstrated efficacy^Citation150
Pirfenidone	Antifibrotic/anti-inflammatory	Pirfenidone effectively prevented bleomycin-induced^Citation183 or cyclophosphamide- induced pulmonary fibrosis^Citation184	The clinical trial is currently recruiting and may be useful to treat lung fibrosis^Citation185
Prednisone	Immunosuppressant	Not tested	Promotes renal complications in SSc patients^Citation148
Relaxin	Modulation of systemic and vascular tone	Relaxin abrogated bleomycin-induced lung fibrosis^Citation138	Initial studies demonstrated efficacy in SSc;^Citation186 however a larger comprehensive cohort failed to show efficacy^Citation170
Rilonacept	A fusion protein between IL-1 receptor and IL-1 accessory protein	Not tested	Currently recruiting SSc patients and no data are available for this drug (NCT01538719)
Rituximab	Targets B-cells	Not tested	A moderately large cohort showed reduced fibrosis and inhibition of worsening of disease when treated with rituximab^Citation187
Terguride	Serotonin inhibitor	Terguride effectively reduced skin fibrosis in the bleomycin model^Citation188	An ongoing clinical trial since 2010 in Europe, but no data have been published to date
Thalidomide	Not completely known, but thought to be an IL-6 inhibitor or a Th1/Th2 modulator	Thalidomide successfully reduced pulmonary fibrosis^Citation189 Pomalidomide, an analog of thalidomide, effectively reduced skin fibrosis^Citation190	Clinical trial for thalidomide was terminated due to difficulty in recruiting subjects A pomalidomide study is currently underway (NCT01559129)

Abbreviations: IL, interleukin; SSc, systemic sclerosis; Tsk1/+, tight skin 1; GVHD, graft versus host disease; TNF, tumor necrosis factor; Th, T helper.

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