Perivascular cells in diffuse cutaneous systemic sclerosis overexpress activated ADAM12 and are involved in myofibroblast transdifferentiation and development of fibrosis

Francesco Ciccia, Giovanni Triolo, Giuliana Guggino, Vasiliki Liakouli, Francesco Carubbi, Paola Di Benedetto, Piero Ruscitti, Onorina Berardicurti, Francesca Zazzeroni, Edoardo Alesse, Roberto Giacomelli, Paola Cipriani

Risultato della ricerca: Article

27 Citazioni (Scopus)

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 á-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.
Lingua originaleEnglish
pagine (da-a)1340-1349
Numero di pagine10
RivistaTHE JOURNAL OF RHEUMATOLOGY
Volume43
Stato di pubblicazionePublished - 2016

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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    Ciccia, F., Triolo, G., Guggino, G., Liakouli, V., Carubbi, F., Di Benedetto, P., Ruscitti, P., Berardicurti, O., Zazzeroni, F., Alesse, E., Giacomelli, R., & Cipriani, P. (2016). Perivascular cells in diffuse cutaneous systemic sclerosis overexpress activated ADAM12 and are involved in myofibroblast transdifferentiation and development of fibrosis. THE JOURNAL OF RHEUMATOLOGY, 43, 1340-1349.