Fibrosis in scleroderma

Systemic sclerosis or scleroderma is a systemic autoimmune disease in which fibrosis of skin, vasculature, and major organs may lead to severe disability and death. The accumulation of increased extracellular matrix proteins is largely the result of increased fibroblast biosynthetic activity regulated at the gene transcriptional level. Fibroblast interactions with activated immune cells and their products (cytokines), endothelial cells, and matrix components contribute to the altered fibroblast phenotype in vivo. In addition, enhanced fibroblast responsiveness to transforming growth factor-beta, differentiation of fibroblasts to myofibroblasts, resistance to apoptosis, and induction of autocrine signaling pathways may lead to overgrowth or selection of high-collagen expressing fibroblasts. The final expression of an abnormal genetic profile at the cellular level may thus become independent of exogenous stimuli and contribute to the maladaptive fibrosis of scleroderma. Identification of metabolic pathways that lead to pathologic fibrosis may allow the application of targeted therapies for the disease.