Targeting the DNM3OS / miR-199a~214 cluster for the treatment of fibroproliferative diseases
Year: 2018
Type: preprint
Abstract: Given the paucity of effective treatments for fibrotic disorders, new insights into the deleterious mechanisms controlling fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Here, we identified the long non-coding RNA DNM3OS as a critical downstream effector of TGF-β-induced myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to 3 distinct profibrotic mature miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which influence both SMAD and non-SMAD components of TGF-β signaling in a multifaceted way, through two modes of action consisting of either signal amplification or mediation. Finally, we provide preclinical evidence that interfering with DNM3OS function using distinct strategies not only prevents lung and kidney fibrosis but also improves established lung fibrosis, providing thus a novel paradigm for the treatment of refractory fibrotic diseases such as idiopathic pulmonary fibrosis. One Sentence Summary The DNM3OS lncRNA is a reservoir of fibromiRs with major functions in fibroblast response to TGF-β and represents a valuable therapeutic target for refractory fibrotic diseases such as idiopathic pulmonary fibrosis (IPF).
DOI: 10.1101/242040
Authors: G. Savary, M. Buscot, E. Dewaeles, S. Diazzi, N. Nottet, E. Courcot, J. Fassy, K. Lebrigand, I. S. Henaoui, N. Martis, C. Van der Hauwaert, S. Leroy, L. Plantier, A. Paquet, C. L. Lino Cardenas, G. Vassaux, B. Crestani, B. Wallaert, R. Rezzonico, T. Brousseau, F. Glowacki, S. Bellusci, M. Perrais, F. Broly, P. Barbry, C. H. Marquette, C. Cauffiez, B. Mari, N. Pottier
Institutions: Centre National de la Recherche Scientifique, Université Côte d'Azur, Université de Lille, Institut de Pharmacologie Moléculaire et Cellulaire, IMPact de l'Environnement Chimique sur la Santé, Centre Hospitalier Universitaire de Nice, Université de Tours, Inserm, Centre d'Étude des Pathologies Respiratoires, Assistance Publique – Hôpitaux de Paris, Hôpital Bichat-Claude-Bernard, Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris Diderot, Centre Hospitalier Universitaire de Lille, Justus-Liebig-Universität Gießen, German Center for Lung Research, Centre de Recherche Jean Pierre Aubert
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2786049253