Joachim Høg Mortensen

The collagen turnover profile is altered in patients with inguinal and incisional hernia

BACKGROUND Disturbed metabolism in the extracellular matrix (ECM) contributes to formation of abdominal wall hernias. The aim of this study was to gain deeper insight into the ECM turnover in hernia patients by analyzing serum biomarkers specifically reflecting collagen synthesis and breakdown in the interstitial matrix (types I, III, and V collagens) and in the basement membrane (type IV collagen). MATERIAL AND METHODS Patients with 3 different types of hernias were included: Primary unilateral inguinal hernia (n = 17), multiple hernias defined as ≥3 hernias (n = 21), and incisional hernia (n = 25). Patients without hernias scheduled to undergo elective operation for gallstones (n = 18) served as controls. Whole venous blood was collected preoperatively. Biomarkers for synthesis of interstitial matrix (PINP, Pro-C3, P5CP) and basement membrane (P4NP) as well as corresponding degradation (C1M, C3M, C5M, and C4M) were measured in serum by validated, solid-phase competitive assays. RESULTS In inguinal hernia patients, the turnover of the interstitial matrix collagens type III (P < .042) and V (P < .001) was decreased compared with controls, whereas the turnover of the basement membrane collagen type IV was increased (P < .001). In incisional hernia patients, the turnover of type V collagen was decreased (P = .048) and the turnover of type IV collagen was increased compared with the hernia-free controls (P < .001). CONCLUSION Hernia patients demonstrated systemically altered collagen metabolism. The serologic turnover profile of type IV collagens may predict the presence of inguinal and incisional hernia. Regulation of type IV collagen turnover may be crucial for hernia development.

Fragments of Citrullinated and MMP-degraded Vimentin and MMP-degraded Type III Collagen Are Novel Serological Biomarkers to Differentiate Crohn’s Disease from Ulcerative Colitis

BACKGROUND AND AIMS A hallmark of inflammatory bowel disease [IBD] is chronic inflammation, which leads to excessive extracellular matrix [ECM] remodelling and release of specific protein fragments, called neoepitopes. We speculated that the biomarker profile panel for ulcerative colitis [UC] and Crohns disease [CD] represent a heterogeneous expression pattern, and may be applied as a tool to aid in the differentiation between UC and CD. METHODS Serum biomarkers of degraded collagens I, III-IV [C1M, C3M, and C4M], collagen type 1 and IV formation [P1NP, P4NP], and citrullinated and MMP-degraded vimentin [VICM] were studied with a competitive ELISA assay system in a cohort including 164 subjects [CD n = 72, UC n = 60, and non-IBD controls n = 32] and a validation cohort of 61 subjects [CD n = 46, and UC n = 15]. Receiver operating characteristic curve analysis and logistic regression modelling were carried out to evaluate the discriminative power of the biomarkers. RESULTS All biomarkers were corrected for confounding factors. VICM and C3M demonstrated the highest diagnostic power, alone, to differentiate CD from UC with an area under the curve [AUC] of 0.77 and 0.69, respectively. Furthermore, the biomarkers C1M [AUC = 0.81], C3M [AUC = 0.83], VICM [AUC = 0.83], and P1NP [AUC = 0.77] were best to differentiate UC from non-IBD. The best combinations of biomarkers to differentiate CD from UC and UC from non-IBD were VICM, C3M, C4M [AUC = 0.90] and VICM, C3M [AUC = 0.98] respectively. CONCLUSIONS Specific extracellular matrix degradation markers are elevated in IBD and can discriminate CD from UC and UC from non-IBD controls with a high diagnostic accuracy.

Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn's disease

Misbalances in extracellular matrix turnover are key factors in the development of stricturing (Montreal B2) and penetrating (Montreal B3) Crohns disease.

Ulcerative colitis, Crohn's disease, and irritable bowel syndrome have different profiles of extracellular matrix turnover, which also reflects disease activity in Crohn's disease

Background Increased protease activity is a key pathological feature of inflammatory bowel disease (IBD). However, the differences in extracellular matrix remodelling (ECM) in Crohn’s disease (CD) and ulcerative colitis (UC) are not well described. An increased understanding of the inflammatory processes may provide optimized disease monitoring and diagnostics. We investigated the tissue remodelling in IBD and IBS patients by using novel blood-based biomarkers reflecting ECM remodelling. Methods Five ECM biomarkers (VICM, BGM, EL-NE, C5M, Pro-C5) were measured by competitive ELISAs in serum from 72 CD patients, 60 UC patients, 22 patients with irritable bowel syndrome (IBS), and 24 healthy donors. One-way analysis of variance, Mann-Whitney U-test, logistic regression models, and receiver operator characteristics (ROC) curve analysis was carried out to evaluate the diagnostic accuracy of the biomarkers. Results The ECM remodelling was significantly different in UC compared to CD. The best biomarker combination to differentiate UC from CD and colonic CD was BGM and VICM (AUC = 0.98, P<0.001; AUC = 0.97, P<0.001), and the best biomarker combination to differentiate IBD from IBS patients were BGM, EL-NE, and Pro-C5 (AUC = 0.8, P<0.001). When correcting for the use of immunosuppressant and elevated CRP levels (CRP>5mg/mL), correlation of Pro-C5 (r = 0.36) with CDAI was slightly improved compared to CRP (r = 0.27) corrected for the use of immunosuppressant. Furthermore, BGM and EL-NE biomarkers were highly associated with colon inflammation in CD patients. Conclusion ECM fragments of tissue remodelling in IBD affect UC and CD differently, and may aid in differentiating IBD from IBS (EL-NE, BGM, Pro-C5), and UC from CD patients (BGM, VICM). Formation of type V collagen is related to the level of inflammation in CD and may reflect disease activity in CD.

Serum type XVI collagen is associated with colorectal cancer and ulcerative colitis indicating a pathological role in gastrointestinal disorders

Altered extracellular matrix (ECM) remodeling is an important part of the pathology of gastrointestinal (GI) disorders. In the intestine, type XVI collagen (col‐16) plays a role in pathogenesis by affecting ECM architecture and induce cell invasion. Measuring col‐16 in serum may therefore have biomarker potential in GI disorders such as colorectal cancer (CRC) and ulcerative colitis (UC). The aim of this study was to determine whether col‐16 can serve as a biomarker for altered ECM remodeling in patients with CRC and UC. A monoclonal antibody was raised against the C‐terminal end of col‐16 (PRO‐C16), and a competitive enzyme‐linked immunosorbent assay (ELISA) was developed and technically validated. Levels of PRO‐C16 were measured in serum from patients with CRC (before (n = 50) and 3 months after (n = 23) tumor resections), UC (n = 39) and healthy controls (n = 50). The PRO‐C16 ELISA was specific toward the C‐terminal of col‐16. PRO‐C16 was significantly elevated both in serum from patients with CRC (P = 0.0026) and UC (P < 0.0001) compared to controls. No difference was detected in levels of PRO‐C16 between patients with CRC at baseline and 3 months after tumor resections (P > 0.999). Levels of PRO‐C16 identified patients with a GI disorder with a positive predictive value of 0.9 and an odds ratio of 12 (95%CI = 4.5‐29.5, P < 0.0001). The newly developed assay detected significantly elevated levels of PRO‐C16 in serum from patients with GI disorders compared to controls suggesting its potential as a biomarker in this setting. Future studies are needed to validate these findings.