Progressive fibrosis of the skin and of various internal organs, notably, the lungs, heart and gastrointestinal tract, is the pathologic hallmark of systemic sclerosis (SSc) (for reviews see references 28, 126, 165, 169). The fibrotic process results in disruption of the normal architecture of the affected organs, and ultimately leads to their dysfunction and failure. Wall fibrosis of medium and small size arterioles is also a prominent alteration in SSc and is likely to play a crucial role in the pathogenesis of pulmonary hypertension, renal crisis, myocardial dysfunction, and digital gangrene in this disease. Thus, it is clear that excessive collagen deposition in affected tissues is a central event in the pathogenesis of SSc and is responsible for most of the clinical manifestations of this incurable disease. The extent and rate of progression of the fibrotic process are major factors in determining the course and prognosis of SSc. As will be discussed in greater detail, numerous studies have established that skin and visceral fibroblasts in SSc display a biosynthetically activated phenotype producing increased amounts of collagen and other components of the extracellular matrix. Whereas the initial event(s) responsible for fibroblast activation in SSc is (are) not known, it is likely that the profound alterations in fibroblast biosynthetic phenotype are crucial elements in the pathogenesis of SSc. Indeed, it is the persistent activation of the genes encoding multiple extracellular matrix proteins in SSc fibroblasts that distinguishes controlled repair, such as that occurring during normal wound healing, from uncontrolled connective tissue accumulation that results in the pathologic fibrosis characteristic of SSc.

Inflammatory cell-derived soluble mediators can influence fibroblast growth, differentiation, and chemotaxis, as well as connective tissue macromolecule synthesis. Compelling evidence indicates that certain cytokines and growth factors are involved in the pathogenesis of the fibrotic process in SSc. It is not known, however, whether aberrant production or activation of these mediators, altered fibroblast responsiveness to the mediators, or impaired down-regulation of fibrogenic stimuli is responsible for the uncontrolled connective tissue accumulation observed in SSc.

Pharmacologic manipulation of the multiple steps involved in the complex pathway leading to exaggerated fibrogenesis offers a potentially successful approach to SSc treatment. Therefore, an understanding of the intimate mechanisms responsible for the abnormalities in the regulation of fibroblast function in SSc may lead to the rational design of novel therapeutic interventions. In this article, we review the regulation of the normal homeostasis of collagen production and the alterations in these regulatory mechanisms that may be responsible for the exaggerated accumulation of collagen in affected tissues in SSc.