Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway
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...
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2021.683267/full |
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| author | Caijuan Huan Wangting Xu Yaru Liu Kexin Ruan Yueli Shi Hongqiang Cheng Xue Zhang Yuehai Ke Jianying Zhou |
| author_facet | Caijuan Huan Wangting Xu Yaru Liu Kexin Ruan Yueli Shi Hongqiang Cheng Xue Zhang Yuehai Ke Jianying Zhou |
| author_sort | Caijuan Huan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T18:55:16Z |
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| id | doaj.art-16d21e8c07804c7da1ebe346a29fbc2b |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-14T18:55:16Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-16d21e8c07804c7da1ebe346a29fbc2b2022-12-21T22:51:07ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2021-06-01810.3389/fmolb.2021.683267683267Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein PathwayCaijuan Huan0Wangting Xu1Yaru Liu2Kexin Ruan3Yueli Shi4Hongqiang Cheng5Xue Zhang6Yuehai Ke7Jianying Zhou8Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaThe Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, ChinaDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaIdiopathic 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.https://www.frontiersin.org/articles/10.3389/fmolb.2021.683267/fullIPF (idiopathic pulmonary fibrosis)gremlin2BMP antagonistsP-smad1fibroblast |
| spellingShingle | Caijuan Huan Wangting Xu Yaru Liu Kexin Ruan Yueli Shi Hongqiang Cheng Xue Zhang Yuehai Ke Jianying Zhou Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway Frontiers in Molecular Biosciences IPF (idiopathic pulmonary fibrosis) gremlin2 BMP antagonists P-smad1 fibroblast |
| title | Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway |
| title_full | Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway |
| title_fullStr | Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway |
| title_full_unstemmed | Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway |
| title_short | Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway |
| title_sort | gremlin2 activates fibroblasts to promote pulmonary fibrosis through the bone morphogenic protein pathway |
| topic | IPF (idiopathic pulmonary fibrosis) gremlin2 BMP antagonists P-smad1 fibroblast |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2021.683267/full |
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