Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway.

Caijuan Huan,Wangting Xu,Yaru Liu,Xue Zhang,Kexin Ruan,Hongqiang Cheng,Jianying Zhou,Yuehai Ke,Yueli Shi

doi:10.3389/fmolb.2021.683267

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.

Highlights

Idiopathic pulmonary fibrosis (IPF), is the most common form of interstitial pneumonia (ATS/ERS, 2000), which deteriorates rapidly in a short period of time (Martinez et al, 2005) and the median survival is only 2–3 years (Raghu et al, 2011).Tissue fibrosis is an increasing cause of severe morbidity and mortality with limited therapeutic options, and IPF is characterized by patchy subpleural parenchymal fibrosis with pathological features including the accumulation of myofibroblasts, the formation of fibroblast foci, distortion of pulmonary architecture, and increased collagen deposition (Noble et al, 2012)
To discern the importance of Gremlin2 in pulmonary fibrosis, we evaluated the expression of Gremlin2 using the GEO database and selected two fibrosis-related databases, GSE99621
GSE10667 exhibited that the transcription level of Gremlin2 in the lung tissues of patients with IPF was significantly higher than that of healthy people (Figure 1A, p < 0.001)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF), is the most common form of interstitial pneumonia (ATS/ERS, 2000), which deteriorates rapidly in a short period of time (Martinez et al, 2005) and the median survival is only 2–3 years (Raghu et al, 2011).Tissue fibrosis is an increasing cause of severe morbidity and mortality with limited therapeutic options, and IPF is characterized by patchy subpleural parenchymal fibrosis with pathological features including the accumulation of myofibroblasts, the formation of fibroblast foci, distortion of pulmonary architecture, and increased collagen deposition (Noble et al, 2012). Mechanisms leading to severe and progressive fibrosis are not entirely understood. Fibroblasts are the main effector cells in fibrosis. They migrate from different sources to damaged sites, such as resident stromal fibroblasts, circulating fibroblasts, as well as epithelial cells and pericytes, and they are eventually activated as myofibroblasts (Andersson-Sjöland et al, 2008; Fernandez and Eickelberg, 2012; Wolters et al, 2014; Bagnato and Harari, 2015), which secrete excessive extracellular matrix (ECM), resulting in increased tissue hardness and loss of alveolar tissue function. The progression of fibrosis is regulated by the transforming growth factor-β (TGF-β)/bone morphogenic protein (BMP) family

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