Pathogenesis of scleroderma. Collagen.
It is now evident that persistent overproduction of collagen and other connective tissue macromolecules results in excessive tissue deposition, and is responsible for the progressive nature of fibrosis in SSc. Up-regulation of collagen gene expression in SSc fibroblasts appears to be a critical event in the development of tissue fibrosis. The coordinate transcriptional activation of a number of extracellular matrix genes suggests a fundamental alteration in the regulatory control of gene expression in SSc fibroblasts. Trans-acting nuclear factors that bind to cis-acting elements in enhancer and promoter regions of the genes modulate the basal and inducible transcriptional activity of the collagen genes. The identity of the nuclear transcriptional factors that regulate normal collagen gene expression remains to be firmly established, and to date, no alterations in the level or in the activity of such DNA binding factors has been demonstrated in SSc fibroblasts. In addition to important interactions between fibroblasts and the extracellular matrix, cytokines and other cellular mediators can positively and negatively influence fibroblast collagen synthesis. Some of these signaling molecules may have physiologic roles, and their aberrant expression, or altered responsiveness of SSc fibroblasts to them, may result in the acquisition of the activated phenotype. The rapid expansion of knowledge regarding the effects of cytokines on extracellular matrix synthesis has led to an appreciation of the enormous complexity of regulatory networks that operate in the physiologic maintenance of connective tissue and which may be responsible for the occurrence of pathologic fibrosis. The ubiquitous growth factor TGF beta is the most potent inducer of collagen gene expression and connective tissue accumulation yet discovered. The expression of TGF beta in activated infiltrating mononuclear cells suggests a role for this cytokine as a mediator of fibroblast activation in SSc. Furthermore, the recognition that TGF beta is capable of inducing its own expression in a variety of cell types, coupled with the demonstration that a subpopulation of SSc dermal fibroblasts produces TGF beta, indicates the existence of a possible autocrine loop whereby lymphocyte-derived TGF beta in early SSc not only signals biosynthetic activation of fibroblasts in a paracrine manner, but autoinduces endogenous TGF beta production by the target fibroblasts themselves. Such an autocrine loop involving TGF beta may explain the persistent activation of collagen gene expression in SSc fibroblasts, and could be responsible for the progressive nature of fibrosis in SSc. Numerous other cytokines, as well as cell-matrix interactions, also modify collagen gene expression and can significantly influence the effects of TGF beta. Although their physiologic function in tissue remodeling or their involvement in abnormal fibrogenesis has not yet been conclusively demonstrated, the study of the biologic effects of these cytokines may provide important clues to understanding the pathogenesis of SSc, and to the development of rational drug therapy aimed at interrupting the abnormal fibrogenic process in this disease.
Jimenez
S A
SA
Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Hitraya
E
E
Varga
J
J
D000818:Animals; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D007372:Interferons / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D012190:Retroviridae; D012595:Scleroderma, Systemic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014764:Viral Proteins
D016207:Cytokines; D006133:Growth Substances; D007375:Interleukin-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D003094:Collagen; D007372:Interferons