Abstract
Objective
To explore the potential roles of Dickkopf-1 (DKK-1) and β-catenin in Crohn disease, and to evaluate the effects of a tumor necrosis factor (TNF)-α inhibitor on Wnt signaling in patients with the disease.
Methods
We enrolled 21 patients who received infliximab treatment for one year and achieved clinical remission during the treatment period. Disease activity was graded according to the Pediatric Crohn’s Disease Activity Index (PCDAI). Peripheral blood and colonic mucosal specimens were collected from all patients with Crohn disease and from 14 healthy controls. DKK-1 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA). Total RNA for DKK-1 and β-catenin from the frozen colonic tissue were obtained via real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), and albumin were also measured in patients with Crohn disease before and after infliximab therapy.
Results
The serum levels of DKK-1 were significantly higher in patients with Crohn disease than in healthy controls (P=0.003) and were decreased in those treated with infliximab (P=0.026). Serum DKK-1 level was correlated with levels of ESR (r=0.527, P=0.025), CRP (r=0.502, P=0.034), albumin (r=0.363, P=0.021) and PCDAI (r =0.462, P=0.054) in Crohn disease. DKK-1 mRNA expression in the colonic mucosa was higher in patients than in controls and decreased after infliximab treatment. β-catenin expression in the colonic mucosa was lower in patients than in controls and increased after infliximab treatment. However, the differences were not significant (P>>0.05).
Conclusions
DKK-1 might be an important mediator of the pathogenesis of Crohn disease, and changes in DKK-1 levels may serve as biomarkers of inflammation in these patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–24.
Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.
Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2000;51:289–98.
Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.
Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.
Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004;5:691–701.
Willert K, Jones KA. Wnt signaling: is the party in the nucleus? Genes Dev. 2006;20:1394–404.
Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro D P, et al. Isolation and biochemical characterization of the human Dkk-1 homologue, a novelinhibitor of mammalian Wnt signaling. J Biol Chem. 1999;274:19465–72.
Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 1998;391:357–62.
Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene. 2006;25:7469–81.
de Lau W, Barker N, Clevers H. WNT signaling in the normal intestine and colorectal cancer. Front Biosci. 2007;12:471–91.
Pinto D, Clevers H. Wnt control of stem cells and differentiation in the intestinal epithelium. Exp Cell Res. 2005;306:357–63.
Inflammatory bowel disease in children and adolescents: Recommendations for diagnosis-the Porto criteria. J Pediatr Gastroenterol Nutr. 2005;41:1–7.
Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, et al. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr. 1991;12:439–47.
Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, et al. Regulation of Wnt signaling during adipogenesis. J Biol Chem. 2002;277:30998–1004.
Miyaoka T, Seno H, Ishino H. Increased expression of Wnt-1 in schizophrenic brains. Schizophr Res. 1999;38:1–6.
Jaworski T, Dewachter I, Lechat B, Gees M, Kremer A, Demedts D, et al. GSK-3alpha/beta kinases and amyloid production in vivo. Nature. 2011;480:E4–5; discussion E6.
Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, et al. DKK1, anegative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene. 2004;23:8520–6.
Gonzalez-Sancho JM, Aguilera O, Garcia JM, Pendas-Franco N, Pena C, Cal S, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene. 2005;24:1098–103.
Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–63.
Funding
Funding: This work was supported by the research fund of Chungnam National University.
Author information
Authors and Affiliations
Contributions
Contributors: Both authors have contributed, designed and approved the final version of manuscript, and are accountable for all aspects related to the study.
Corresponding author
Ethics declarations
Competing interests: None stated.
Rights and permissions
About this article
Cite this article
Kim, M.J., Choe, Y.H. Correlation of Dickkopf-1 with Inflammation in Crohn Disease. Indian Pediatr 56, 929–932 (2019). https://doi.org/10.1007/s13312-019-1649-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13312-019-1649-5