Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets
Background and Aims: Crohn’s disease (CD) can be complicated by intestinal fibrosis. Pharmacological therapies against intestinal fibrosis are not available. The aim of this study was to determine whether pathways involved in collagen metabolism are upregulated in intestinal fibrosis, and to discuss...
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doaj-9e48b0b11a31439f91188307e7e9da022020-11-25T03:49:25ZengSAGE PublishingTherapeutic Advances in Gastroenterology1756-28482020-08-011310.1177/1756284820952578Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targetsWouter Tobias van HaaftenTjasso BlokzijlHendrik Sijbrand HofkerPeter OlingaGerard DijkstraRuud A. BankMiriam BoersemaBackground and Aims: Crohn’s disease (CD) can be complicated by intestinal fibrosis. Pharmacological therapies against intestinal fibrosis are not available. The aim of this study was to determine whether pathways involved in collagen metabolism are upregulated in intestinal fibrosis, and to discuss which drugs might be suitable to inhibit excessive extracellular matrix formation targeting these pathways. Methods: Human fibrotic and non-fibrotic terminal ileum was obtained from patients with CD undergoing ileocecal resection due to stenosis. Genes involved in collagen metabolism were analyzed using a microfluidic low-density TaqMan array. A literature search was performed to find potential anti-fibrotic drugs that target proteins/enzymes involved in collagen synthesis, its degradation and its recognition. Results: mRNA expression of collagen type I ( COL1A1 , 0.76 ± 0.28 versus 37.82 ± 49.85, p = 0.02) and III ( COL3A1 , 2.01 ± 2.61 versus 68.65 ± 84.07, p = 0.02) was increased in fibrotic CD compared with non-fibrotic CD. mRNA expression of proteins involved in both intra- and extracellular post-translational modification of collagens (prolyl- and lysyl hydroxylases, lysyl oxidases, chaperones), collagen-degrading enzymes (MMPs and cathepsin-K), and collagen receptors were upregulated in the fibrosis-affected part. A literature search on the upregulated genes revealed several potential anti-fibrotic drugs. Conclusion: Expression of genes involved in collagen metabolism in intestinal fibrosis affected terminal ileum of patients with CD reveals a plethora of drug targets. Inhibition of post-translational modification and altering collagen metabolism might attenuate fibrosis formation in the intestine in CD. Which compound has the highest potential depends on a combination anti-fibrotic efficacy and safety, especially since some of the enzymes play key roles in the physiology of collagen.https://doi.org/10.1177/1756284820952578 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wouter Tobias van Haaften Tjasso Blokzijl Hendrik Sijbrand Hofker Peter Olinga Gerard Dijkstra Ruud A. Bank Miriam Boersema |
spellingShingle |
Wouter Tobias van Haaften Tjasso Blokzijl Hendrik Sijbrand Hofker Peter Olinga Gerard Dijkstra Ruud A. Bank Miriam Boersema Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets Therapeutic Advances in Gastroenterology |
author_facet |
Wouter Tobias van Haaften Tjasso Blokzijl Hendrik Sijbrand Hofker Peter Olinga Gerard Dijkstra Ruud A. Bank Miriam Boersema |
author_sort |
Wouter Tobias van Haaften |
title |
Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets |
title_short |
Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets |
title_full |
Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets |
title_fullStr |
Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets |
title_full_unstemmed |
Intestinal stenosis in Crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets |
title_sort |
intestinal stenosis in crohn’s disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets |
publisher |
SAGE Publishing |
series |
Therapeutic Advances in Gastroenterology |
issn |
1756-2848 |
publishDate |
2020-08-01 |
description |
Background and Aims: Crohn’s disease (CD) can be complicated by intestinal fibrosis. Pharmacological therapies against intestinal fibrosis are not available. The aim of this study was to determine whether pathways involved in collagen metabolism are upregulated in intestinal fibrosis, and to discuss which drugs might be suitable to inhibit excessive extracellular matrix formation targeting these pathways. Methods: Human fibrotic and non-fibrotic terminal ileum was obtained from patients with CD undergoing ileocecal resection due to stenosis. Genes involved in collagen metabolism were analyzed using a microfluidic low-density TaqMan array. A literature search was performed to find potential anti-fibrotic drugs that target proteins/enzymes involved in collagen synthesis, its degradation and its recognition. Results: mRNA expression of collagen type I ( COL1A1 , 0.76 ± 0.28 versus 37.82 ± 49.85, p = 0.02) and III ( COL3A1 , 2.01 ± 2.61 versus 68.65 ± 84.07, p = 0.02) was increased in fibrotic CD compared with non-fibrotic CD. mRNA expression of proteins involved in both intra- and extracellular post-translational modification of collagens (prolyl- and lysyl hydroxylases, lysyl oxidases, chaperones), collagen-degrading enzymes (MMPs and cathepsin-K), and collagen receptors were upregulated in the fibrosis-affected part. A literature search on the upregulated genes revealed several potential anti-fibrotic drugs. Conclusion: Expression of genes involved in collagen metabolism in intestinal fibrosis affected terminal ileum of patients with CD reveals a plethora of drug targets. Inhibition of post-translational modification and altering collagen metabolism might attenuate fibrosis formation in the intestine in CD. Which compound has the highest potential depends on a combination anti-fibrotic efficacy and safety, especially since some of the enzymes play key roles in the physiology of collagen. |
url |
https://doi.org/10.1177/1756284820952578 |
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