Genetic and molecular drivers of scleroderma pathogenesis

Scleroderma is a heterogeneous disease with various clinical findings involving immune dysregulation, vasculopathy, and fibrosis. Biological and genetic studies over recent decades have elucidated molecular mechanisms of scleroderma pathogenesis. Genetic association studies have identified interferon and other immune regulatory genes as strongly linked to scleroderma risk, highlighting the immune system as a fundamental determinant of disease. Human and murine biological studies have identified growth factor signaling as a central feature linking tissue damage to the clinical phenotype. Growth factors activated in vascular endothelial cells overlap with those of other diseases having vascular abnormalities, such as hereditary hemorrhagic telangiectasia. Activated growth factor receptors in fibroblasts drive excessive collagen expression in the skin and lungs. Because growth factor signaling is overactivated in multiple malignancies, biological insights and therapeutic approaches may be translated from oncology to understand scleroderma better. Enhanced understanding of the molecular drivers of scleroderma pathogenesis has given greater insight into patient phenotypes and new therapeutic approaches, including those that target immune and growth factor signaling.