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

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.

SUBMITTER: Huan C

PROVIDER: S-EPMC8377751 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Huan Caijuan C Xu Wangting W Liu Yaru Y Ruan Kexin K Shi Yueli Y Cheng Hongqiang H Zhang Xue X Ke Yuehai Y Zhou Jianying J

Frontiers in molecular biosciences 20210628

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. <i>GREM2</i>, initially identified as a TGF-β-inducible gene, encodes a small secreted glycoprotein belonging to a group of matricel ...[more]

PMID: 34422900

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Project description:BackgroundPeritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats.MethodsTo mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 μg/Kg, IP). Animals were followed up for 30 days.ResultsCG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFβ/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression.ConclusionsIn conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process.

Project description:Rationale: During development, the contribution of IL34, a ligand of macrophage colony stimulating factor receptor (MCSFR), has not been fully defined. Together with its twin cytokine MCSF, they display an essential role in macrophage differentiation and activation, including tissue specialized macrophages. The mechanism of action of each molecule involves the phosphorylation of MCSFR in varying intensity and kinetics. Furthermore, IL34 can interact with other receptors and cofactors, opening a wide range of modulations during development. The aim of this work was to investigate these effects through the suppression of IL34 in different animal models and study molecular interactions, with a particular focus on osteoclast / osteoblast regulation. Methods: Two different and unique models of IL34-/- were generated in zebrafish and mouse. The skeleton of both species was analyzed and compared by histological and morphometric (Micro-CT) approaches. The role of IL34 and new partners in osteoclast and osteoblast differentiation was analyzed by multiple techniques including mineralization assays, tartrate resistant acid phosphatase (TRAP) staining, receptor phosphorylation and activation assays, and gene expression (real-time quantitative PCR) studies. Furthermore, protein interactions were studied by surface plasmon resonance approach and protein-protein docking ClusPro analysis. Results: Significant growth delay and hypo-mineralization of skeletal elements were observed in both IL34-/- models, as well as craniofacial dysmorphoses in mice. With regard to bone cells, an unexpected increase in the number of osteoclasts and an accumulation of pre-osteoblasts were observed in mice lacking IL34. For the first time, in vitro analyses complemented by protein binding and molecular docking studies established that IL34 interacts directly with certain Bone Morphogenetic Proteins (BMPs), modulating their various activities such as the stimulation of osteoblast differentiation. Conclusions: A new mechanism of action for IL34 through BMPs has been characterized. IL34 interactions with MCSFR and BMPs appear crucial for both osteoclastogenesis and osteoblastogenesis, impacting bone tissue homeostasis and development. The potential interaction of IL34 with different members of the BMP family and their functional impact, including pathological situations such as cancer, should be further explored, opening new therapeutic perspectives.

Dataset Information

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

Publications

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

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