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Table 1 Scleroderma Genetics Models (Lakos et al. 2004; Jimenez and Christner 2002)

From: Mesenchymal stem cell as a novel approach to systemic sclerosis; current status and future perspectives

Genetic Model Category Specific Features Site of Fibrosis
Tight skin 1 mouse models(Tsk1/+) Models with spontaneous mutations - They are bred as heterozygotes because of lethal homozygous mutation.
- They have thickened skin which is tightly joined to the subcutaneous tissue.
- The deposition of elastin has risen but there isn’t elasticity in the skin.
- They present an emphysema-like pathology in the lung due to the increased elastin.
- They have an enlarged heart and skeleton.
- There is partial duplication of the fibrillin-1 gene as a mutation on chromosome 2 which seems to suppress raised levels of TGFβ in the extracellular matrix and following stimulating collagen synthesis.
Skin
Tight skin 2 mouse models (Tsk2/+) Models with spontaneous mutations - They are generated via mutagenic agent ethylnitrosourea.
- Tight skin can be found in the interscapular region.
- The mutation is placed on chromosome 1.
- They can mimic many characteristics of systemic sclerosis subjects, containing increased deposition of the dermal extracellular matrix, tight skin, and autoantibodies.
- They present enhanced transcription percentages of dermal fibroblasts type I and III collagen.
- Increased autoimmunity have reported in Tsk2/+ models.
Skin
UCD-200 chickens Models with spontaneous mutations - They are identified by infiltration of perivascular lymphocytic, vascular occlusion caused by endothelial injuries, fibrosis of the skin and visceral organs, and spotted antinuclear antibodies.
- There is a genetic defect with an autosomal recessive mode of inheritance or multiple loci interactions.
- Five genes including which have been reported to have importance in the pathology of systemic sclerosis including (TGFBR1, IGFBP3, EXOC2/IRF4, CCR8 (located on chromosome 2), and SOCS1(located at chromosome 14) have been recognized to present a high association with the disease.
- Mutation of COL1A2 gene (located on chromosome 2) may play a role in avian systemic sclerosis.
Skin and Visceral organs
Endothelin-1 mouse models Transgenic models of fibrosis - There is increased expression of endothelin-1.
- They have endothelial dysfunction.
- They develop glomerulosclerosis and interstitial fibrosis.
Kidney and Lung
Fos-related antigen-2 mouse models Transgenic models of fibrosis - There is overexpressing the Fos-related antigen-2 (FRA-2)
- They show microangiopathy along with progression of skin fibrosis.
Skin and Lung
Type I TGFβ receptor transgenic models Transgenic models of fibrosis - There is upregulating of the type I TGFβ receptor in fibroblasts on a Cre-ER transgenic background.
- There are increasing levels of collagen deposition in the skin of through the aging.
Skin
Kinase-deficient type II TGFβ receptor transgenic models Transgenic models of fibrosis - There is a fibroblast-specific transcriptional enhancer (applied to specifically express a kinase-deficient mutant type II TGFβ receptor which can involve TGFβ) upstream of the COL1A2 collagen gene.
- There is the lack of immune activation and autoantibodies.
Skin and Lung
PDGF receptor-α transgenic models of fibrosis Transgenic models of fibrosis - There is conditionally expressed PDGF receptor-α activating mutations. Skin and Internal organs
Caveolin-1 deficient models Knockout models of fibrosis - There are raised collagen and fibronectin accumulation along with increased amounts of myofibroblasts.
- There is oxidative stress condition.
Skin
Early growth response protein-1 knockout mouse models Knockout models of fibrosis - There are reduced amounts of infiltrating inflammatory cells in the skin along with the reduced dermal thickness and expression of collagen. Skin and Lung
Friend leukemia integration factor-1 conditional knockout mouse models Knockout models of fibrosis - There is risen vascular permeability.
- They mimic the collagen fibril formation abnormalities in systemic sclerosis.
Skin
Macrophage chemoattractant protein-1 mouse models Knockout models of fibrosis - There are reduced fibrotic replies after the injection of basic fibroblast growth factor and connective tissue growth factor into the skin.
- There are fewer mast cells, reduction of macrophage recruitment, and fewer CD4+ T-cell amounts.
Skin
Microsomal prostaglandin E2 synthase-1 knockout models Knockout models of fibrosis - There are bleomycin-induced fibrosis resistant, α-smooth muscle actin levels reduction, and macrophages numbers reduction. Skin and Lung
Peroxisome proliferator-activated receptor-gamma deficient models Knockout models of fibrosis - There is more extensive skin thickening with bleomycin compared to wild-type.
- They can help to determine the function of this protein in collagen synthesis.
Skin
PTEN conditional knockout mouse models Knockout models of fibrosis - There are developed thickened skin and collagen deposition along with raised α-smooth muscle actin-bearing fibroblasts numbers, connective tissue growth factor-positive fibroblasts, and proliferating cell nuclear antigen-positive fibroblasts. Skin
Relaxin knockout mouse models Knockout models of fibrosis - There is developed skin collagen deposition over time. Skin
  1. Tsk1/+ Tight skin1 mouse, Tsk2/+ Tight skin2 mouse, TGFβ Transforming growth factor beta, TGFBR1 Transforming Growth Factor Beta Receptor 1, IGFBP3 Insulin-like growth factor-binding protein 3, CCR3 C-C chemokine receptor type 3, SOCS1 Suppressor of cytokine signaling 1, COL1A2 Collagen Type I Alpha 2 Chain, FRA-2 Fos-related antigen-2, ER Estrogen Receptor, PDGF Platelet-derived growth factor