Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis

Human Collagen Krox Up-regulates Type I Collagen Expression in Normal and Scleroderma Fibroblasts through Interaction with Sp1 and Sp3 Transcription Factors

“…Interestingly, during the first stages of scleroderma disease, an accumulation of CD4ϩ lymphocytes is observed, whereas CD8ϩ population is decreased. CD4ϩ cells migrate in vascular epithelium and dermis connective tissues and lead to an activation of target cells and to an increased production of pro-fibrogenic growth factors and cytokines (22,54). Taken together, these data suggest that hc-Krox could be one of the first actors involved in the manifestation of scleroderma, playing a role in the immune reaction but also in the remodeling of dermis ECM.…”

“…Sp1 and Sp3 are ubiquitous proteins belonging to the family of Sp transcription factors recognizing GC and TC boxes, like c-Krox (22). Sp1 is a well characterized activator of type I collagen genes (6,12,(23)(24)(25); however, its function seems to depend on the cellular and/or molecular context.…”

“…It has been shown to inhibit mouse Col1a1 gene in NIH-3T3 fibroblasts (26) and to function as a co-inhibitor of human COL1A2 gene transcription when it interacts with the transcription factor Fli-1 in human skin fibroblasts (27). Additionally, Sp1 may play a role in fibrotic diseases, because it is one of the mediators of transforming growth factor-␤1, a profibrogenic factor that activates human COL1A1 gene transcription (10,22,28). In this regard, its binding activity is increased in human scleroderma fibroblasts and in hepatic stellate cells, compared with normal cells (23,29).…”

Cytokines in the immunopathology of systemic sclerosis

“…SSc patients are found to have impaired secretion of potent vasodilators by the endothelial cells such as nitric oxide, prostacyclin and calcitonin gene-related peptide. The altered endothelial cells also produce ET-1 which has vasoconstrictor properties that contributes to vascular hypoxia leading to both vascular dysfunction and fibroblast activation, thus maintaining a vicious cycle between these two processes [96]. Derangements in nitric oxide (NO) and superoxide anions are also thought to be of significance in altered vascular tone in SSc [97].…”

Pathogenese der systemischen Sklerodermie

“…Die systemische Sklerodermie ist eine Multisystemerkrankung mit progredientem, potenziell tödlichem Verlauf [14]. Charakteristisch ist das initiale Auftreten eines Raynaud-Syndroms, gefolgt von einer ödematösen Schwellung v. a. der Finger, Hände und Unterarme.…”