Paola Cipriani1, Paola Di Benedetto1, Piero Ruscitti1, Vasiliki Liakouli1, Onorina Berardicurti1, Francesco Carubbi1, Francesco Ciccia1, Giuliana Guggino1, Francesca Zazzeroni1, Edoardo Alesse1, Giovanni Triolo1, Roberto Giacomelli1. 1. From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila, L'Aquila; Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo, Palermo, Italy.P. Cipriani, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; P. Di Benedetto, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; V. Liakouli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; O. Berardicurti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; F. Ciccia, MD, PhD, Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo; G. Guggino, MD, Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; G. Triolo, MD, PhD, Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School
Abstract
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-β (TGF-β). 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-β 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-β by immunofluorescence, quantitative real-time PCR, and western blot. Further, we silenced ADAM12 expression in both dcSSc-MSC and -FB to confirm the TGF-β modulation. RESULTS: Pericytes and FB of dcSSc skin showed an increased expression of ADAM12 when compared with healthy control skin. TGF-β 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-β ability to upregulate α-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-β, while increasing ADAM12 expression, may modulate this transdifferentiation.
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-β (TGF-β). 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-β 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-β by immunofluorescence, quantitative real-time PCR, and western blot. Further, we silenced ADAM12 expression in both dcSSc-MSC and -FB to confirm the TGF-β modulation. RESULTS: Pericytes and FB of dcSSc skin showed an increased expression of ADAM12 when compared with healthy control skin. TGF-β 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-β ability to upregulate α-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-β, while increasing ADAM12 expression, may modulate this transdifferentiation.
Authors: P Cipriani; R Giacomelli; P Di Benedetto; P Ruscitti; O Berardicurti; M Vomero; L Navarini; V Dolo Journal: Clin Exp Immunol Date: 2021-04-18 Impact factor: 5.732
Authors: Tong Jiao; Ye Yao; Bo Zhang; Da-Cheng Hao; Qing-Feng Sun; Jing-Bo Li; Chao Yuan; Bao Jing; Yun-Peng Wang; Hai-Yang Wang Journal: Biomed Res Int Date: 2017-03-05 Impact factor: 3.411