Overview of animal models

The ability to sample fibrotic tissue in systemic sclerosis (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 tissues. It is noteworthy that the activated pathways are largely overlapping with the biological responses during normal wound healing, but in contrast to physiological tissue responses to injury, they are not effectively terminated, but become chronically activated. In addition to defining these components of the SSc disease process, skin biopsy material has also proven valuable as a starting point to identify deregulated signaling cascades and to generate novel hypotheses. To test the importance of a candidate pathway, process, or mediator, it is necessary to explore the relevance experimentally. While experiments on cellular components isolated from affected tissues such as primary fibroblasts are essential to provide first proof of concept, there is a pressing need to further validate the results in vivo. Animal models of SSc are crucially required to close the gap between in vitro studies and clinical trials.