Overview of animal models

Abstract

The ability to sample lesional tissue in SSc by performing skin biopsy has been a major strength in trying to understand the pathobiology of this disease in comparison to other forms of organ-based fibrosis. It has permitted the identification of cardinal histological features of scleroderma and has defined key phases of the pathology in a temporal sequence so that there is now a clear understanding that as the disease develops, the first changes occur at the level of the dermal microcirculation followed by the development of inflammation that first involves cells of the innate immune and later adaptive immune system. Finally, there is the fibrotic stage of the disease that results in the replacement of specialized structures with rather vascular fibrotic connective tissue. The final component is the most important in determining the morbidity and mortality of SSc as it occurs in all target organs and tissue including the vasculature. It is noteworthy that these processes are to a large extent reminiscent of the biological responses to tissue damage and in the skin to the cardinal processes that permit healing of a full-thickness skin wound. In addition to defining these components of the SSc disease process, skin biopsy material has also proven valuable as a starting point for discovery studies using new technological approaches such as unbiased screening or gene or protein expression, and for studies of protein modification, epigenetics, and signaling pathway activity. These approaches are essentially hypothesis generating. To test the importance of a candidate pathway, process, or mediator, it is necessary to explore the relevance experimentally. This can be done in vitro, and skin biopsies have helped here too. Cellular components, especially fibroblasts, may be cultured form biopsies, and these can be examined in the same ways as whole skin and also subjected to pharmacological or biological modulation. This approach has been taken to test candidate molecular therapeutics for SSc skin disease. However, there is a pressing need to perform experiments in vivo. Ultimately, this may be through clinical trials, and there are already examples of this in SSc. This is seen in studies that have examined prostanoids, angiotensin receptor blockers, and endothelin receptor antagonists, for example. The findings from such clinical studies can themselves inform on pathogenic mechanisms through reverse translation. However, there is a clear need for robust animal models to help dissect out hallmark pathogenic process in SSc and to provide a platform for preclinical examination of candidate novel therapeutics before they are tested in human studies.