The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair

Gastroenterology. 2011 Jul;141(1):259-68, 268.e1-8. doi: 10.1053/j.gastro.2011.03.043. Epub 2011 Mar 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Azoxymethane
  • Cell Proliferation
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / metabolism*
  • Colitis / pathology
  • Colon / metabolism*
  • Colon / pathology
  • Colorectal Neoplasms / chemically induced
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Down-Regulation
  • Homeostasis
  • Injections, Intraperitoneal
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / immunology
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Signal Transduction
  • Time Factors
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / metabolism*
  • Wound Healing*
  • beta Catenin / metabolism

Substances

  • Antibodies, Monoclonal
  • CTNNB1 protein, mouse
  • Dkk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Wnt Proteins
  • beta Catenin
  • Dextran Sulfate
  • Azoxymethane