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Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts

Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferati...

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Autores principales: Peterson, Joshua M., Jay, Jayson W., Wang, Ye, Joglar, Alejandro A., Prasai, Anesh, Palackic, Alen, Wolf, Steven E., El Ayadi, Amina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223605/
https://www.ncbi.nlm.nih.gov/pubmed/35743131
http://dx.doi.org/10.3390/ijms23126689
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author Peterson, Joshua M.
Jay, Jayson W.
Wang, Ye
Joglar, Alejandro A.
Prasai, Anesh
Palackic, Alen
Wolf, Steven E.
El Ayadi, Amina
author_facet Peterson, Joshua M.
Jay, Jayson W.
Wang, Ye
Joglar, Alejandro A.
Prasai, Anesh
Palackic, Alen
Wolf, Steven E.
El Ayadi, Amina
author_sort Peterson, Joshua M.
collection PubMed
description Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-β and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 μM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars.
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spelling pubmed-92236052022-06-24 Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts Peterson, Joshua M. Jay, Jayson W. Wang, Ye Joglar, Alejandro A. Prasai, Anesh Palackic, Alen Wolf, Steven E. El Ayadi, Amina Int J Mol Sci Article Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-β and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 μM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars. MDPI 2022-06-15 /pmc/articles/PMC9223605/ /pubmed/35743131 http://dx.doi.org/10.3390/ijms23126689 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Peterson, Joshua M.
Jay, Jayson W.
Wang, Ye
Joglar, Alejandro A.
Prasai, Anesh
Palackic, Alen
Wolf, Steven E.
El Ayadi, Amina
Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts
title Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts
title_full Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts
title_fullStr Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts
title_full_unstemmed Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts
title_short Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts
title_sort galunisertib exerts antifibrotic effects on tgf-β-induced fibroproliferative dermal fibroblasts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223605/
https://www.ncbi.nlm.nih.gov/pubmed/35743131
http://dx.doi.org/10.3390/ijms23126689
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