Dataset Information

Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohn's disease.

ABSTRACT:

Background

Increased collagen remodelling is a key pathophysiological component underlying intestinal stricture and fistula development in Crohn's disease (CD).

Aims

To investigate associations between serological biomarkers of collagen turnover and disease behaviour according to the Montreal classification in patients with CD.

Methods

Serological biomarkers of type III/IV collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP) or granzyme-B (GrzB)-mediated type I, III, IV and VI collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) were measured using neo-epitope protein fingerprint assays in 101 patients with CD (Montreal B1: n = 37; B2: n = 27; B3: n = 37) and 96 controls. Patients were followed up until their last outpatient visit to monitor stricturing/penetrating disease progression and recurrence and the occurrence of surgical interventions.

Results

C1M, C3M and C4M were significantly reduced in patients with stricturing disease (Montreal B2) and accurately differentiated them from patients with either non-stricturing, non-penetrating (B1) or penetrating (B3) disease (all p < 0.001, multivariable analysis). Similarly, the type IV collagen formation/degradation (PRO-C4/C4M) ratio demonstrated high discriminative capacity (B1/B2: AUC = 0.90; B1/B3: AUC = 0.87, both p < 0.001, multivariable analysis). Prospectively, higher baseline levels of C1M and C4G were associated with an increased risk of penetrating disease progression (C4G: hazard ratio [HR] 1.71 [1.05-2.81], p < 0.05).

Conclusions

Elevated degradation of type I, III and IV collagen and excessive (relative) formation of type IV collagen strongly associates with stricturing CD. Type I and IV collagen fragments show predictive potential for the risk of penetrating disease progression. These biomarkers may become valuable tools for detection and prediction of stricturing and penetrating CD.

SUBMITTER: Bourgonje AR

PROVIDER: S-EPMC9544881 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohn's disease.

Bourgonje Arno R AR Alexdottir Marta S MS Otten Antonius T AT Loveikyte Roberta R Bay-Jensen Anne-Christine AC Pehrsson Martin M van Dullemen Hendrik M HM Visschedijk Marijn C MC Festen Eleonora A M EAM Weersma Rinse K RK Karsdal Morten A MA Faber Klaas Nico KN Mortensen Joachim H JH Dijkstra Gerard G

Alimentary pharmacology & therapeutics 20220606 4

<h4>Background</h4>Increased collagen remodelling is a key pathophysiological component underlying intestinal stricture and fistula development in Crohn's disease (CD).<h4>Aims</h4>To investigate associations between serological biomarkers of collagen turnover and disease behaviour according to the Montreal classification in patients with CD.<h4>Methods</h4>Serological biomarkers of type III/IV collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP) or granzyme-B (GrzB)-mediated t ...[more]

PMID: 35661188

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Project description:Increased TGF-β1 and TGF-β1-dependent Collagen I production in intestinal mesenchymal cells result in fibrosis in patients with Montreal B2 fibrostenotic Crohn's disease. Numerous cytokines, including IL-6, are produced by activated mesenchymal cells themselves and activate STAT3. The aim of the current study was to determine the mechanisms by which STAT-3 activation might result in intestinal fibrosis. Cytokine levels were measured by ELISA. STAT3 and suppressor of cytokine signaling 3 protein levels were measured by immunoblot, STAT3-TGFB1 DNA-binding activity by chromatin immunoprecipitation, and TGFB1 transcriptional activity by luciferase reporter assay. TGF-β1 (TGFB1), Collagen1α1, and connective tissue growth factor (CTGF) gene expression was measured by quantitative RT-PCR. The role of STAT3 activation was determined using STAT3 inhibitor, Stattic, and by transfection of STAT3 mutants. Autocrine production of cytokines was increased in muscle cells of B2 phenotype patients from strictures and normal intestine in the same patient and compared with other Crohn's phenotypes, ulcerative colitis, and non-Crohn's patients. A unique pattern of STAT3 phosphorylation emerged: high STAT3(S727) and low STAT3(Y705) in strictures and the opposite in unaffected intestine. TGFB1 transcriptional activity was regulated by phospho-STAT3(S727) and was decreased by Stattic or dominant-negative STAT3(S727A). TGF-β1, COL1A1, and CTGF expression was inhibited by Stattic or dominant-negative STAT3(S727A). Treatment of normal muscle cells with IL-6 or expression of constitutively active STAT3(S727E) phenocopied muscle cells from strictured intestine. Neutralization of autocrine IL-6 reversed STAT3 phosphorylation and normalized expression of TGF-β1 in strictured intestinal muscle. The ability of Stattic to improve development of fibrosis was confirmed in mice with 2,4,6-trinitrobenzenesulfonic acid-induced colitis. We observed a unique phospho-STAT3(S727) response in patients with Montreal B2 Crohn's disease, particularly in response to IL-6 leading to increased TGF-β1, collagen, and CTGF production in ileal strictures.

Dataset Information

Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohn's disease.

Background

Aims

Methods

Results

Conclusions

Publications

Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohn's disease.

Similar Datasets

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