Elevated expression of cav-1 in a subset of SSc fibroblasts contributes to constitutive Alk1/Smad1 activation.
Bottom Line: We show that a significant subset of SSc dermal fibroblasts has up-regulated cav-1 expression in vitro, and that cav-1 up-regulation correlates with constitutive Smad1 phosphorylation.We also show that cav-1 is a positive regulator of CCN2 gene expression, and that it is required for the basal and TGFβ-induced CCN2 levels.In conclusion, this study has revealed an important role of cav-1 in mediating TGFβ/Smad1 signaling and CCN2 gene expression in healthy and SSc dermal fibroblasts.
Affiliation: Arthritis Center-Rheumatology, Boston University School of Medicine, Boston, MA 02118, USA.Show MeSH
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Mentions: As the majority of SSc cell lines express higher levels of cav-1 than matched, healthy dermal fibroblasts (Fig. 1), we next examined cav-1 in the skin of seven SSc patients and eight healthy controls, using immunohistochemistry. The demographic characteristics of the patients are summarized in Table 1. Representative staining from the skin of SSc and healthy controls is shown in Figure 5. An average of 200 fibroblasts were counted in each specimen and scored as described in materials and methods, and the summary of the results is included in Table 1. Staining revealed heterogeneity of cav-1 expression among SSc and control skin sections. Although cav-1 was expressed at high levels in blood vessels, the majority of SSc and healthy skin fibroblasts showed low levels of cav-1 in vivo. In addition, although SSc fibroblasts had higher expression of cav-1 in culture, when matched for gender, race and age, this pattern was only observed in some of the healthy skin biopsies (Fig. 5 and Table 1). The average intensity of staining in blood vessels from SSc skin was slightly decreased compared to control, however, this result did not reach statistical significance. Our present results show that cav-1 is neither consistently down-regulated nor up-regulated in SSc skin in vivo. This result is in contradiction with the conclusion by Del Galdo et al., showing that fibroblasts from SSc biopsies express cav-1 at lower levels . One potential explanation is that for that study the investigators used a small sample size of only three SSc and three control biopsies, compared to the sample size used in our study, which was larger (seven SSc and eight healthy biopsies).
Affiliation: Arthritis Center-Rheumatology, Boston University School of Medicine, Boston, MA 02118, USA.