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GSK-3β in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1–dependent mechanism
Mohit Kapoor, … , David J. Abraham, Andrew Leask
Mohit Kapoor, … , David J. Abraham, Andrew Leask
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3279-3290. https://doi.org/10.1172/JCI35381.
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Research Article Dermatology

GSK-3β in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1–dependent mechanism

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Abstract

Glycogen synthase kinase–3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3β in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic α-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 (ET-1) compared with control mice and cells. Antagonizing ET-1 reversed the phenotype of Gsk3b-CKO fibroblasts and mice. Thus, GSK-3β appears to control the progression of wound healing and fibrosis by modulating ET-1 levels. These results suggest that targeting the GSK-3β pathway or ET-1 may be of benefit in controlling tissue repair and fibrogenic responses in vivo.

Authors

Mohit Kapoor, Shangxi Liu, Xu Shi-wen, Kun Huh, Matthew McCann, Christopher P. Denton, James R. Woodgett, David J. Abraham, Andrew Leask

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Figure 7

Loss of GSK-3β results in increased ET-1 expression.

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Loss of GSK-3β results in increased ET-1 expression.
(A) ET-1 protein ex...
(A) ET-1 protein expression. Western blot analysis showed a significant (P < 0.05) increase in the protein expression of ET-1 in day 7 wounds of Gsk3b-CKO compared with Gsk3b-C mice. Representative data for n = 8 animals per group are shown. (B) ET-1 immunohistochemistry. Higher expression levels of ET-1 were detected in day 7 wounds of Gsk3b-CKO compared with Gsk3b-C mice. Representative data for n = 4 animals per group are shown. Arrows indicate ET-1–positive staining. Scale bar: 100 μm. (C) ET-1 mRNA expression was assessed in Gsk3b-CKO versus Gsk3b-C fibroblasts by real-time PCR. Gsk3b-CKO fibroblasts showed significantly (P < 0.05) higher expression of ET-1 mRNA versus Gsk3b-C fibroblasts (n = 4 cell lines from 4 mice). (D) ET-1 ELISA. ET-1 levels were assessed in the cell culture supernatants of Gsk3b-CKO versus Gsk3b-C fibroblasts by ELISA. Gsk3b-CKO fibroblasts showed significantly (P < 0.05) higher levels of ET-1 versus Gsk3b-C fibroblasts (n = 6 cell lines from 6 mice). *P < 0.05.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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