Genetic models for connective tissue disease, scarring and fibrosis

When vital organs are damaged in disease this results in the development of scar tissue. When the scar is excessive or disporportionate this can itself worsen organ function, a process termed fibrosis. Fibrosis is a result of altered or abnormal healing processes and is a common factor in many common diseases. Less common disorders such as scleroderma (also called systemic sclerosis) cause fibrois in multiple organs including the skin, lungs, heart and blood vessels. We have developed, for the first time, models of fibrotic disease that can be used to study the development and consequences of fibrosis in the skin and internal organs. Through understanding these models, it is very likely that better methods for assessment and treating fibrosis will emerge.

Fibrosis occurs due to excessive or inappropriate deposition of extracellular matrix in affected tissues. Systemic sclerosis is an uncommon rheumatic disease in which susceptibility to skin and visceral fibrosis leads to high mortality and morbidity. Key fibrotic mediators have been identified in SSc, including TGFbeta and CTGF. It is likely that overactivity of these mediators, or their downstream pathways, underlies the development of fibrosis in SSc and that this may also be relevant to other forms of fibrotic disease. We have developed 3 unique mouse models of fibrotic disease that recapitulate cardinal features of SSc including skin and lung fibrosis and vasculopathy. We will use these models to extend and validate molecular and imaging strategies that complement those used in human disease. The first model uses fibroblast-specific expression of a non-signalling type II TGFbeta receptor to increase constitutive TGFbeta activity in connective tissue in a ligand-dependent fashion. This leads to skin fibrosis and increased susceptibility to lung injury. The second mouse strain permits conditional fibroblast-specific high level activation of TGFbeta signalling that is ligand independent. A Cre-Lox strategy is used for fibroblast specific expression of a constitutively active mutant type I TGFbeta receptor. This strain develops marked skin and vascular fibrosis. A hallmark of both of these mouse stains is upregulation of CTGF. In the third model we have overexpressed CTGF in fibroblasts and again observe a severe skin fibrosis.
Together these complementary strains will be used to explore development of SSc associated autoantibodies and to ask whether the gene and protein expression in affected mouse organs replicates that of human SSc. A comparison of markers from these mouse models with those from scleroderma patients should increase our understanding of the diverse disease phenotypes of human scleroderma. In addition we will translate recent clinical advances in SSc assessment into these mouse strains, including novel imaging modalities, to provide a platform for future testing of targeted anti-fibrotic therapies.