Scleroderma fibroblasts exhibit numerous phenotypic differences when compared with healthy skin fibroblasts. Some of these differences, in particular overexpression of collagen type I and other extracellular matrix proteins, parallel the effect of transforming growth factor-beta (TGF-beta) on dermal fibroblasts, suggesting that the scleroderma fibroblast phenotype may result from activation of autocrine TGF-beta signaling. To test this hypothesis we examined the role of TGF-beta Type I and Type II receptors in regulating collagen type I transcription. We have shown that overexpression of either Type I or Type II receptors significantly (3-4-fold) increases alpha2 (I) collagen promoter activity in transient transfection assays in dermal fibroblasts. Addition of anti-TGF-beta antibody abolished, whereas addition of plasmin enhanced, the stimulatory effect of receptor overexpression on collagen promoter activity, suggesting that this effect depends on autocrine TGF-beta. Moreover, these cotransfection experiments indicated that expression levels of TGF-beta receptors is a limiting factor in the autocrine regulation of collagen type I transcription by TGF-beta. Comparison of the TGF-beta receptor Type I and Type II mRA expression levels in scleroderma and normal fibroblasts have indicated elevated expression (2-fold) of both receptor types in scleroderma cells, which correlated with increased binding of TGF-beta. Significantly, elevated TGF-beta receptor levels correlated with elevated alpha2 (I) collagen mRNA levels. These results suggest that the elevated production of collagen type I by scleroderma fibroblasts results from overexpression of TGF-beta receptors.

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Capillary blood flow in nailfold capillaries, observed continuously by capillary microscopy during standardized cold exposure (16 °C) has been compared in 15 patients with scleroderma (SD), 6 patients with Raynaud’s syndrome (RS) without known organic pathology, and 9 normal controls. Capillary microscopy affords direct observation of capillary blood flow and allows one to determine if standstill of capillary circulation occurs (as defined by the movement of the red blood cell column), a state impossible to differentiate from near zero flow by conventional methods. Complete standstill of capillary blood flow occurred in 10 of 15 patients with SD and in 1 of 6 patients with RS. Intermittent standstill was observed in 5 of 15 SD and in 4 of 6 RS patients. In all normal subjects and in 1 of 6 patients with RS the capillary blood flow continued throughout the cooling period. Thus all 15 patients with SD and 5 of 6 patients with RS could be distinguished from control subjects by the development of capillary standstill on cooling. It is concluded that capillary microscopy can separate SD and RS patients from control subjects during cold exposure and may be useful in early diagnosis and prognosis of rheumatic syndromes and in the evaluation of therapy designed to improve the nutritional capillary blood flow of the skin. Whereas the complete standstill of capillary blood flow appears to be definitely associated with pathology, the intermittent standstill pattern as defined in this study may be an exaggerated form of flow fluctuation also seen in normal subjects. A larger number of subjects will have to be studied to determine whether patients with RS of the vasospastic type without connective tissue disease can be distinguished from normal subjects with low finger blood flow rates in cold conditions.