Fibrillin-1 protein in tight skin mice and scleroderma.

Abstract

Scleroderma (SSc) is a complex and clinically heterogenous disease of unknown origin, in which both genetic and environmental factors appear to be implicated. In addition to skin, other internal organs, including lung, heart, intestine, and kidney, can be affected. Vascular injuries represent one of the earliest events in SSc, which is followed by proliferation of fibroblasts and excessive production of extracellular matrix proteins (ECM) leading to fibrosis, the end point of disease. SSc is also associated with alteration of microfibrils in which fibrillin (Fbn-1) is a major component. The overproduction of ECM proteins is related to an increased expression of genes encoding ECM proteins such as collagen type I, III, V, VI, fibronectin fibrillin, tenascin, and osteonectin. The synthesis of glycoaminoglycans is also increased (1). SSc is associated with autoimmunity as illustrated by infiltration of afflicted organs with lymphocytes and macrophages in the early inflammatory phase, (2) increased levels of cytokines (3), and autoantibodies mainly specific for nuclear antigens (4). Experimental models of human diseases particularly genetic ones related to a single gene defect represented excellent biological tools to study the pathogenesis of human diseases. In the case of SSc, the tight skin (TSK) murine mutant strain represents the best animal model and has been the most extensively investigated. Mice develop a scleroderma-like syndrome, resembling human scleroderma (4) and congenital fascial dystrophy (5). Clinical Reviews in Allergy and Immunology © Copyright 2000 by Humana Press Inc. 1080–0549/00/119–126 $12.00