• Grégoire Savary, Edmone Dewaeles, Serena Diazzi, Matthieu Buscot, Nicolas Nottet, Julien Fassy, Elisabeth Courcot, Imène-Sarah Henaoui, Julie Lemaire, Nihal Martis, Cynthia Van der Hauwaert, Nicolas Pons, Virginie Magnone, Sylvie Leroy, Véronique Hofman, Laurent Plantier, Kevin Lebrigand, Agnès Paquet, Christian L Lino Cardenas, Georges Vassaux, Paul Hofman, Andreas Günther, Bruno Crestani, Benoit Wallaert, Roger Rezzonico, Thierry Brousseau, François Glowacki, Saverio Bellusci, Michael Perrais, Franck Broly, Pascal Barbry, Charles-Hugo Marquette, Christelle Cauffiez, Bernard Mari, and Nicolas Pottier.
• 1 CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, FHU-OncoAge, Université Côte d'Azur, Valbonne, France.
• Am. J. Respir. Crit. Care Med. 2019 Jul 15; 200 (2): 184-198.

AbstractRationale: Given the paucity of effective treatments for idiopathic pulmonary fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. TGF-β (transforming growth factor-β) is the main profibrotic factor, but its inhibition is associated with severe side effects because of its pleiotropic role. Objectives: To determine if downstream noncoding effectors of TGF-β in fibroblasts may represent new effective therapeutic targets whose modulation may be well tolerated. Methods: We investigated the whole noncoding fraction of TGF-β-stimulated lung fibroblast transcriptome to identify new genomic determinants of lung fibroblast differentiation into myofibroblasts. Differential expression of the long noncoding RNA (lncRNA) DNM3OS (dynamin 3 opposite strand) and its associated microRNAs (miRNAs) was validated in a murine model of pulmonary fibrosis and in IPF tissue samples. Distinct and complementary antisense oligonucleotide-based strategies aiming at interfering with DNM3OS were used to elucidate the role of DNM3OS and its associated miRNAs in IPF pathogenesis. Measurements and Main Results: We identified DNM3OS as a fibroblast-specific critical downstream effector of TGF-β-induced lung myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to three distinct profibrotic mature miRNAs (i.e., miR-199a-5p/3p and miR-214-3p), which influence SMAD and non-SMAD components of TGF-β signaling in a multifaceted way. In vivo, we showed that interfering with DNM3OS function not only prevents lung fibrosis but also improves established pulmonary fibrosis. Conclusions: Pharmacological approaches aiming at interfering with the lncRNA DNM3OS may represent new effective therapeutic strategies in IPF.

26 keywords...

hide…