Modulation of Collagen Gene Expression: Its Relation to Fibrosis in Systemic Sclerosis and Other Disorders
Posted Sep 11 2009 4:56pm
Fibrosis is the pathologic hallmark of many common diseases. Much information has recently emerged about the cellular and biochemical events that result in its development and progression. It is now known that in affected tissues, chronic inflammation generally precedes fibrosis and that inflammatory cell-derived cytokines are crucial mediators of fibrogenesis.
Several cytokines have been identified that influence wound healing and tissue repair processes in vivo and that modulate the production of collagen in vitro. Of these, transforming growth factor-ß is of the most interest because this pleiotropic cytokine is expressed at high levels during tissue remodeling and greatly affects the formation of connective tissue.
Furthermore, it has been recently shown that transforming growth factor-ß can stimulate the transcription of collagen genes through the production or activation of specific DNA-binding trans-acting factors. A precise understanding of the molecular mechanisms responsible for the effects of this cytokine on collagen gene expression may allow the design of selective therapeutic interventions aimed at retarding or preventing the development of fibrosis.
Substantial progress has been made in the understanding of the complex interplay among inflammatory cells, fibroblasts, and the extracellular matrix and of how this interplay affects reparative and fibrogenic responses. Fibrosis is the pathologic hallmark of many human diseases, including pulmonary fibrosis, hepatic cirrhosis, chronic glomerulonephritis, postsurgical adhesions, and arterial restenosis after angioplasty. Systemic sclerosis (scleroderma) is a prototypic fibrotic disease in which the skin, lungs, heart, gastrointestinal tract, and kidneys are major targets for progressive and often relentless fibrosis.
A simplified view of the regulation of collagen gene transcription, the process that leads to production of collagen from the initial template of the collagen gene. Transcription of the collagen gene is initiated by binding of the transcription initiation complex, which contains RNA polymerase II and various initiation factors, to the DNA (upper panel). This basal level of transcription is markedly stimulated by transforming growth factor-ß, which may cause binding of transcriptional regulatory factors (shaded ovals) to upstream promoter elements and to upstream or intronic enhancer DNA sequences. Binding of the transcriptional factors may result in looping of DNA, allowing distant transcriptional regulatory factors to contact the transcription initiation complex (lower panel).