Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis
| Autor: | Stefan Pryzborski, Max Brown, Jörg H W Distler, Steven O'Reilly, Lena Summa, John Henderson, Richard Stratton, Nicola Fullard, Laura Duffy |
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| Rok vydání: | 2021 |
| Předmět: |
collagen
0301 basic medicine QH301-705.5 medicine.medical_treatment B100 Bone morphogenetic protein Cell and Developmental Biology 03 medical and health sciences 0302 clinical medicine Fibrosis medicine BMP ddc:610 Biology (General) Original Research ECM gremlin-1 Chemistry C100 fibrosis Cell Biology Transfection medicine.disease Connective tissue disease B900 CTGF 030104 developmental biology Cytokine 030220 oncology & carcinogenesis Cancer research Gremlin (protein) Myofibroblast Developmental Biology |
| Zdroj: | Frontiers in Cell and Developmental Biology Frontiers in Cell and Developmental Biology, 2021, Vol.9, pp.681061 [Peer Reviewed Journal] Frontiers in Cell and Developmental Biology, Vol 9 (2021) |
| ISSN: | 2296-634X |
| DOI: | 10.3389/fcell.2021.681061 |
| Popis: | ObjectiveSystemic Sclerosis is an autoimmune connective tissue disease which results in fibrosis of the skin and lungs. The disease is characterized by activation of myofibroblasts but what governs this is unknown. Gremlin-1 is a BMP antagonist that is developmentally regulated and we sought to investigate its role in Systemic Sclerosis.MethodsDermal fibroblasts were transfected with Grem1pcDNA3.1 expression vectors or empty vectors. Various markers of myofibroblasts were measured at the mRNA and protein levels. Scratch wound assays were also performed. Media Transfer experiments were performed to evaluate cytokine like effects. Various inhibitors of TGF-β signaling and MAPK signaling were used post-transfection. siRNA to Gremlin-1 in SSc dermal fibroblasts were performed to evaluate the role of Gremlin-1. Different cytokines were incubated with fibroblasts and Gremlin-1 measured. Bleomycin was used as model of fibrosis and immunohistochemistry performed.ResultsOverexpression of Gremlin-1 was achieved in primary dermal fibroblasts and lead to activation of quiescent cells to myofibroblasts indicated by collagen and α-Smooth muscle actin. Overexpression also led to functional effects. This was associated with increased TGF-β1 levels and SBE luciferase activity but not increased Thrombospondin-1 expression. Inhibition of Gremlin-1 overexpression cells with antibodies to TGF-β1 but not isotype controls led to reduced collagen and various TGF-β pathway chemical inhibitors also led to reduced collagen levels. In SSc cells siRNA mediated reduction of Gremlin-1 reduced collagen expression and CTGF gene and protein levels in these cells. IL-13 did not lead to elevated Gremlin-1 expression nor did IL-11. Gremlin-1 was elevated in an animal model of fibrosis compared to NaCl-treated mice.ConclusionGremlin-1 is a key regulator of myofibroblast transition leading to enhanced ECM deposition. Strategies that block Gremlin-1 maybe a possible therapeutic target in fibrotic diseases such as SSc. |
| Databáze: | OpenAIRE |
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