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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 1

Conditional deletion of Gsk3b in fibroblasts.

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Conditional deletion of Gsk3b in fibroblasts.
   
(A) PCR analysis of ge...
(A) PCR analysis of genomic DNA isolated from tails of Col1a2-creER(T)/0; Gsk3bF/F mice treated with corn oil (Gsk3b-C) or tamoxifen (Gsk3b-CKO) for 1 week. Col1a2-creER(T)/0; Gsk3bF/F mice treated with tamoxifen generated fibroblast-specific CKO mice. All genomic DNA samples were run on the same gel. Genotype of mice: lanes 1–3, Col1a2-creER(T)/0; Gsk3bF/F mice; lanes 4 and 5, Gsk3bF/F mice (B). GSK-3β immunofluorescence (in vivo). Immunofluorescence using GSK-3β antibody in day 0 unwounded skin of Gsk3b-C and Gsk3b-CKO mice. Scale bars: top row, 200 μm; bottom row, 100 μm. White arrows indicate GSK-3β–positive staining in the epidermis; yellow arrow, GSK-3β–positive staining in the dermis; blue arrows, GSK-3β–positive staining in hair follicles. Representative data from n = 4 animals per group are shown. (C) Percentage of GSK-3β–positive fibroblasts in Gsk3b-C versus Gsk3b-CKO mice. (D) GSK-3β immunofluorescence (in vitro). Immunofluorescence using GSK-3β antibody in dermal fibroblasts isolated from Gsk3b-C and -CKO mice. Representative data from n = 8 cell lines from 8 mice. Scale bar: 50 μm. (E) Loss of GSK-3β protein expression in fibroblasts isolated from Gsk3b-CKO mice. n = 8 cell lines from 8 mice is shown. *P < 0.05.

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