Journal
JOURNAL OF RHEUMATOLOGY
Volume 43, Issue 7, Pages 1340-1349Publisher
J RHEUMATOL PUBL CO
DOI: 10.3899/jrheum.150996
Keywords
SYSTEMIC SCLEROSIS; PERICYTE; FIBROSIS
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Objective. Microvascular damage is pivotal in the pathogenesis of systemic sclerosis ( SSc), preceding fibrosis, and whose trigger is not still fully understood. Perivascular progenitor cells, with profibrotic activity and function, are identified by the expression of the isoform 12 of ADAM ( ADAM12) and this molecule may be upregulated by transforming growth factor-beta ( TGF-beta). The goal of this work was to evaluate whether pericytes in the skin of patients with diffuse cutaneous SSc ( dcSSc) expressed ADAM12, suggesting their potential contribution to the fibrotic process, and whether TGF-beta might modulate this molecule. Methods. After ethical approval, mesenchymal stem cells ( MSC) and fibroblasts ( FB) were isolated from bone marrow and skin samples collected from 20 patients with dcSSc. ADAM12 expression was investigated in the skin and in isolated MSC and FB treated with TGF-beta by immunofluorescence, quantitative real-time PCR, and western blot. Further, we silenced ADAM12 expression in both dcSSc-MSC and -FB to confirm the TGF-beta modulation. Results. Pericytes and FB of dcSSc skin showed an increased expression of ADAM12 when compared with healthy control skin. TGF-beta in vitro treatment induced a significant increase of ADAM12 in both SSc-MSC and -FB, with the higher levels observed in dcSSc cells. After ADAM12 silencing, the TGF-beta ability to upregulate alpha-smooth muscle actin in both SSc-MSC and SSc-FB was inhibited. Conclusion. Our results suggest that in SSc, pericytes that transdifferentiate toward activated FB are present in the vascular tree, and TGF-beta, while increasing ADAM12 expression, may modulate this transdifferentiation.
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