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The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Department of Pediatrics, Emory University, Atlanta, Georgia.
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2011 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 141, no 1, 259-268 p.Article in journal (Refereed) Published
Abstract [en]

Background & Aims

Dkk1 is a secreted antagonist of the Wnt/β-catenin signaling pathway. It is induced by inflammatory cytokines during colitis and exacerbates tissue damage by promoting apoptosis of epithelial cells. However, little is known about the physiologic role of Dkk1 in normal intestinal homeostasis and during wound repair following mucosal injury. We investigated whether inhibition of Dkk1 affects the morphology and function of the adult intestine.

Methods

We used doubleridge mice (Dkk1d/d), which have reduced expression of Dkk1, and an inhibitory Dkk1 antibody to modulate Wnt/β-catenin signaling in the intestine. Intestinal inflammation was induced with dextran sulfate sodium (DSS), followed by a recovery period in which mice were given regular drinking water. Animals were killed before, during, or after DSS administration; epithelial homeostasis and the activity of major signaling pathways were investigated by morphometric analysis, bromo-2′-deoxyuridine incorporation, and immunostaining.

Results

Reduced expression of Dkk1 increased proliferation of epithelial cells and lengthened crypts in the large intestine, which was associated with increased transcriptional activity of β-catenin. Crypt extension was particularly striking when Dkk1 was inhibited during acute colitis. Dkk1d/dmice recovered significantly faster from intestinal inflammation but exhibited crypt architectural irregularities and epithelial hyperproliferation compared with wild-type mice. Survival signaling pathways were concurrently up-regulated in Dkk1d/d mice, including the AKT/β-catenin, ERK/Elk-1, and c-Jun pathways.

Conclusions

Dkk1, an antagonist of Wnt/β-catenin signaling, regulates intestinal epithelial homeostasis under physiologic conditions and during inflammation. Depletion of Dkk1 induces a strong proliferative response that promotes wound repair after colitis.

Place, publisher, year, edition, pages
Maryland Heights, United States: W.B. Saunders Co. , 2011. Vol. 141, no 1, 259-268 p.
Keyword [en]
IBD, Crohn's Disease, Mucosa, Intestinal Cell Signaling
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-141660DOI: 10.1053/j.gastro.2011.03.043ISI: 000292299700047PubMedID: 21440550Scopus ID: 2-s2.0-79959935078ISBN: 1528-0012 (Electronic) 0016-5085 (Linking) OAI: oai:DiVA.org:liu-141660DiVA: diva2:1149706
Note

Koch, Stefan Nava, Porfirio Addis, Caroline Kim, Wooki Denning, Timothy L Li, Linheng Parkos, Charles A Nusrat, Asma eng R01 DK079392/DK/NIDDK NIH HHS/ R29 DK055679/DK/NIDDK NIH HHS/ R01 DK072564/DK/NIDDK NIH HHS/ DK 072564/DK/NIDDK NIH HHS/ DK 055679/DK/NIDDK NIH HHS/ R01 DK055679/DK/NIDDK NIH HHS/ R01 DK061379/DK/NIDDK NIH HHS/ DK 079392/DK/NIDDK NIH HHS/ DK 061379/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2011/03/29 06:00 Gastroenterology. 2011 Jul;141(1):259-68, 268.e1-8. doi: 10.1053/j.gastro.2011.03.043. Epub 2011 Mar 25.

Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-10-25Bibliographically approved

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