Abstract Introduction: Systemic sclerosis (SSc) is a connective tissue disorder characterized by endothelial cell injury, autoimmunity and fibrosis. The following three fibrillin-1 alterations have been reported in SSc. (1) Fibrillin-1 microfibrils are disorganized in SSc dermis. (2) Fibrillin-1 microfibrils produced by SSc fibroblasts are unstable. (3) Mutations in the FBN1 gene and anti-fibrillin-1 autoantibodies have been reported in SSc. Fibrillin-1 microfibrils, which are abundantly produced by blood and lymphatic microvascular endothelial cells (B-MVECs and Ly-MVECs, respectively), sequester in the extracellular matrix the latent form of the potent profibrotic cytokine transforming growth factor b (TGF-b). In the present study, we evaluated the effects of SSc sera on the deposition of fibrillin-1 and microfibril-associated glycoprotein 1 (MAGP-1) and the expression of focal adhesion molecules by dermal B-MVECs and Ly-MVECs. Methods: Dermal B-MVECs and Ly-MVECs were challenged with sera from SSc patients who were treatment-naïve or under cyclophosphamide (CYC) treatment and with sera from healthy controls. Fibrillin-1/MAGP-1 synthesis and deposition and the expression of avb3 integrin/phosphorylated focal adhesion kinase and vinculin/actin were evaluated by immunofluorescence and quantified by morphometric analysis. Results: Fibrillin-1 and MAGP-1 colocalized in all experimental conditions, forming a honeycomb pattern in B-MVECs and a dense mesh of short segments in Ly-MVECs. In B-MVECs, fibrillin-1/MAGP-1 production and avb3 integrin expression significantly decreased upon challenge with sera from naïve SSc patients compared with healthy controls. Upon challenge of B-MVECs with sera from CYC-treated SSc patients, fibrillin-1/MAGP-1 and avb3 integrin levels were comparable to those of cells treated with healthy sera. Ly-MVECs challenged with SSc sera did not differ from those treated with healthy control sera in the expression of any of the molecules assayed. Conclusions: Because of the critical role of fibrillin-1 in sequestering the latent form of TGF-b in the extracellular matrix, its decreased deposition by B-MVECs challenged with SSc sera might contribute to dermal fibrosis. In SSc, CYC treatment might limit fibrosis through the maintenance of physiologic fibrillin-1 synthesis and deposition by B-MVECs.
Villano, M., Borghini, A., Mirko, M., Gabbrielli, E., Rossi, A., Sestini, P., et al. (2013). Systemic sclerosis sera affect fibrillin-1 deposition by dermal blood microvascular endothelial cells:therapeutic implications of cyclophosphamide. ARTHRITIS RESEARCH & THERAPY, 15, R90.
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|Titolo:||Systemic sclerosis sera affect fibrillin-1 deposition by dermal blood microvascular endothelial cells:therapeutic implications of cyclophosphamide|
|Citazione:||Villano, M., Borghini, A., Mirko, M., Gabbrielli, E., Rossi, A., Sestini, P., et al. (2013). Systemic sclerosis sera affect fibrillin-1 deposition by dermal blood microvascular endothelial cells:therapeutic implications of cyclophosphamide. ARTHRITIS RESEARCH & THERAPY, 15, R90.|
|Appare nelle tipologie:||1.1 Articolo in rivista|
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