AUTHOR=Huan Caijuan , Xu Wangting , Liu Yaru , Ruan Kexin , Shi Yueli , Cheng Hongqiang , Zhang Xue , Ke Yuehai , Zhou Jianying TITLE=Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway JOURNAL=Frontiers in Molecular Biosciences VOLUME=8 YEAR=2021 URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.683267 DOI=10.3389/fmolb.2021.683267 ISSN=2296-889X ABSTRACT=

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing unremitting extracellular matrix deposition. Transforming growth factor-β (TGF-β) superfamily involves bone morphogenetic proteins (BMPs) and TGF-β, and the balance between the activation of TGF-β-dependent SMADs (Smad2/3) and BMP-dependent SMADs (Smad1/5/8) is essential for fibrosis process. GREM2, initially identified as a TGF-β-inducible gene, encodes a small secreted glycoprotein belonging to a group of matricellular proteins, its role in lung fibrosis is not clear. Here, we identified Gremlin2 as a key regulator of fibroblast activation. Gremlin2 was highly expressed in the serum and lung tissues in IPF patients. Bleomycin-induced lung fibrosis model exhibited high expression of Gremlin2 in the bronchoalveolar lavage fluid (BALF) and lung tissue. Isolation of primary cells from bleomycin-induced fibrosis lung showed a good correlation of Gremlin2 and Acta2 (α-SMA) expressions. Overexpression of Gremlin2 in human fetal lung fibroblast 1 (HFL-1) cells increased its invasion and migration. Furthermore, Gremlin2 regulates fibrosis functions through mediating TGF-β/BMP signaling, in which Gremlin2 may activate TGF-β signaling and inhibit BMP signaling. Therefore, we provided in vivo and in vitro evidence to demonstrate that Gremlin2 may be a potential therapeutic target for the treatment of IPF.