The Wnt Antagonist Dkk1 Regulates Intestinal Epithelial Homeostasis and Wound Repair

• Authors: Stefan Koch, Emory University; Porfirio Nava Dominguez, Emory University; Caroline Addis, Emory University; Wooki Kim, Emory University; Timothy Denning, Emory University; Linheng Li, Stowers Institute for Medical Research; Charles Parkos, Emory University; Asma Nusrat, Emory University
• Journal Title: Gastroenterology
• Volume: Volume 141, Number 1
• Publisher: Elsevier: 12 months | 2011-07, Pages 259-268.e8
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1053/j.gastro.2011.03.043
• Subjects: Health Sciences, Pathology
• Keywords: IBD; Crohn’s Disease; Mucosa; Intestinal Cell Signaling

Abstract

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/d mice 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.