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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 2

Loss of GSK-3β expression in fibroblasts results in enhanced wound closure.

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Loss of GSK-3β expression in fibroblasts results in enhanced wound closu...
(A and B) Kinetics of wound closure. Microphotographs of wounds were captured on days 0, 3, 7, and 10 after wounding to determine the degree of wound closure in Gsk3b-CKO compared with Gsk3b-C mice. Total area of wounds at days 0, 3, and 7 after wounding was measured using Northern Eclipse software as described in Methods. Gsk3b-CKO mice showed a significant (P < 0.05) acceleration in wound closure compared with Gsk3b-C mice on days 7 and 10 after wounding. Representative data from n = 8 animals per group are shown. Scale bar: 1 mm. (C and D) Histomorphometric analysis of wound closure. Histomorphometric evaluation of wound closure was performed by measuring the diameter of day 0 and 7 wounds of Gsk3b-CKO versus Gsk3b-C mice. Gsk3b-CKO mice showed a significant (P < 0.05) decrease in wound diameter compared with Gsk3b-C mice on day 7 after wounding. Representative data from n = 6 animals per group are shown. Arrows indicate the leading edges of wounded epidermis. Scale bar: 200 μm. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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