The molecular and cellular mechanisms that maintain proper collagen homeostasis in healthy human skin and are responsible for the dysregulated collagen synthesis in scleroderma remain primarily unknown. This study demonstrates that Fli1 is a physiological negative regulator of collagen gene expression in dermal fibroblasts in vitro and in human skin in vivo.

Objective. To determine whether biopsy specimens obtained from systemic sclerosis (SSc) lesions show a distinctive gene profile, whether that gene profile is maintained in fibroblasts cultured from SSc skin biopsy specimens, and whether results from tissue obtained from multiple clinical centers can be combined to yield useful observations in this rare disease.Methods. Biopsy samples and passaged fibroblasts were stored in RNAlater solution prior to processing for RNA. RNA from SSc and control skin biopsy specimens, as well as SSc and control explanted passage 4 fibroblasts, from 9 patients and 9 controls was hybridized to Affymetrix HG-U133A arrays. Data were analyzed using the BRB ArrayTools system. When appropriate, findings were followed up with immunohistochemical analysis or TaqMan studies.Results. Biopsy samples obtained from patients with SSc had a robust and distinctive gene profile, with ϳ1,800 qualifiers distinguishing normal skin from SSc skin at a significant level. The SSc phenotype was the major driver of sample clusters, independent of origin. Alterations in transforming growth factor ␤ and Wnt pathways, extracellular matrix proteins, and the CCN family were prominent. Explanted fibroblasts from SSc biopsy samples showed a far smaller subset of changes that were relatively variable between samples, suggesting that either nonfibroblast cell types or other aspects of the dermal milieu are required for full expression of the SSc phenotype.Conclusion. SSc has a distinct gene profile that is not confounded by geographic location, indicating that extended multicenter studies may be worthwhile to identify distinct subsets of disease by transcript profiling. Explanted SSc fibroblasts show an incomplete reflection of the SSc phenotype.

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Objective. Aberrant transforming growth factor ␤ (TGF␤) signaling has been implicated in the pathogenesis of scleroderma (systemic sclerosis [SSc]), but the contribution of specific components in this pathway to SSc fibroblast phenotype remains unclear. This study was undertaken to delineate the role of TGF␤ receptor type I (TGF␤RI) and TGF␤RII in collagen overexpression by SSc fibroblasts.Methods. Primary dermal fibroblasts from SSc patients and healthy adults were studied (n ‫؍‬ 10 matched pairs). Adenoviral vectors were generated for TGF␤RI (AdTGF␤RI), TGF␤RII (AdTGF␤RII), and kinase-deficient TGF␤RII (Ad⌬kRII). TGF␤RI basal protein levels were analyzed by 35 S-methionine labeling/ immunoprecipitation and immunohistochemistry. Type I collagen and TGF␤RII basal protein levels were analyzed by Western blot and newly secreted collagen by 3 H-proline incorporation assay.Results. Analysis of endogenous TGF␤RI and TGF␤RII protein levels revealed that SSc TGF␤RI levels were increased 1.7-fold (P ‫؍‬ 0.008; n ‫؍‬ 7) compared with levels in healthy controls, while TGF␤RII levels were decreased by 30% (P ‫؍‬ 0.03; n ‫؍‬ 7). This increased TGF␤RI:TGF␤RII ratio correlated with SSc collagen overexpression. To determine the consequences of altered TGF␤RI:TGF␤RII ratio on collagen expression, healthy fibroblasts were transduced with AdTGF␤RI or AdTGF␤RII. Forced expression of TGF␤RI in the range corresponding to elevated SSc TGF␤RI levels increased basal collagen expression in a dose-dependent manner, while similar TGF␤RII overexpression had no effect, although transduction of fibroblasts at higher multiplicities of infection led to a marked reduction of basal collagen levels. Blockade of TGF␤ signaling via Ad⌬kRII resulted in ϳ50% inhibition of basal collagen levels in healthy fibroblasts and in 5 of 9 SSc cell lines. A subset of SSc fibroblasts (4 of 9 cell lines) was resistant to this treatment. SSc fibroblasts with the highest levels of TGF␤RI were the least responsive to collagen inhibition via ⌬kRII.Conclusion. This study indicates that an increased TGF␤RI:TGF␤RII ratio may underlie aberrant TGF␤ signaling in SSc and contribute to elevated basal collagen production, which is insensitive to TGF␤ signaling blockade via ⌬kRII.Scleroderma (systemic sclerosis [SSc]) is characterized by excessive deposition of extracellular matrix

We report a follow-up of the original case of eruptive multiple keratoacanthoma (KA) described by Grzybowski in 1950 which did not show malignant transformation within 16 years after the onset of the disease in spite of a very widespread cutaneous involvement. There was no associated internal malignancy or any systemic disease either, and the patient died of a myocardial infarction unrelated to his cutaneous disorder. This case followed up for such a long time provides further confirmation that this variety of KA does not show invasive growth and usually does not progress into squamous cell carcinoma