Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis

Veidal, Sanne Skovgård; Karsdal, Morten A.; Nawrocki, Arkadiusz; Larsen, Martin R.; Dai, Yueqin; Zheng, Qinlong; Hägglund, Per; Vainer, Ben; Skjøt‐Arkil, Helene; Leeming, Diana Julie

doi:10.1186/1755-1536-4-22

Cited by 103 publications

(94 citation statements)

References 33 publications

(33 reference statements)

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“…Changes in ACTA2 and COL1A1 expression, further confirmed the progression-and concentration-dependent nature of the fibrogenic response, particularly in MTX-treated tissues. The treatment-induced mobilization of NPCs and activation of HSCs within the tissue were consistent with findings from published clinical studies of progressive fibrosis (Attallah et al, 2007;Veidal et al, 2011). Whereas future studies will expand the genomic, proteomic, and histologic characteristics of the model during progressive fibrotic injury, these initial observations provide encouraging evidence that the model has translational utility.…”

Section: Discussionsupporting

confidence: 74%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate-and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1b) during the early culture time period is followed by concentration-and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-b1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.Key words: liver fibrosis in vitro; 3D bioprinted liver; compound-induced liver injury.Chronic liver injury progressing to fibrosis and liver failure can result from a wide range of insults including drug or chemical exposure, metabolic disease, alcoholism, or viral infection, and is a major health burden worldwide with 2% of all deaths attributable to liver cirrhosis Murray et al., 2012). Whereas the major precipitating factors underlying drug-and chemicalinduced fibrosis have been gleaned from animal models, the key initiating and series of adaptive events that perpetuate this response, especially in humans, are still not well understood. Regardless of etiology, progressive fibrotic liver injury is

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Section: Discussionsupporting

confidence: 74%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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“…These findings are in accordance with previous reports which found elevated levels of type IV collagen in serum from breast and ovarian cancer patients [14,15] and elevated levels of collagen type I and III in the tissue of breast and ovarian cancer patients [7,16]. Furthermore, the desmoplatic reaction in cancer share many similarities with general fibrosis where the fragments of collagen type I [10], type III [11], and type IV [13] also have been found elevated in serum and linked to ECM remodeling.…”

Section: Discussionsupporting

confidence: 82%

“…Using well-characterized and validated competitive ELISAs, levels of MMP 2, 9 and 13-degraded collagen type I (C1M) [10], MMP-9 degraded collagen type III (C3M) [11], and MMP-9 and 12 degraded collagen type IV (C4M, C4M12) [12,13] were assessed in the serum samples.…”

Section: Elisa Measurements and Proceduresmentioning

confidence: 99%

Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study

Bager

Willumsen

Leeming

et al. 2015

CBM

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Abstract. BACKGROUND: During cancer the otherwise tightly controlled homeostasis of the extracellular matrix (ECM) is disturbed. The protein composition changes, the ECM stiffens and increased levels of proteases are secreted. The combination of these processes result in release of specific protein fragments (e.g. collagens) to the circulation, which when measured may reflect disease pathogenesis. OBJECTIVE: To investigate if biomarkers of protease-degraded collagen could differentiate ovarian and breast cancer patients from healthy controls when measured in serum. METHODS: The levels of markers reflecting MMP-degradation of type I (C1M), type III (C3M) and type IV (C4M, C4M12) collagen were assessed in serum from ovarian cancer patients (n = 10), breast cancer patients (n = 14) and healthy controls (n = 49) using validated ELISAs. The markers were compared using one way ANOVA and AUC was calculated. RESULTS: All markers were significantly elevated in serum from ovarian cancer patients (p < 0.0001) and breast cancer patients (p < 0.04-0.0001) compared to healthy controls. Furthermore, diagnostically the markers were able to differentiate ovarian (AUROC 90%-93%) and breast cancer patients (AUROC 76%-93%) from healthy controls, with C1M being the strongest differentiator of disease vs. controls. CONCLUSION: Four serum biomarkers reflecting altered MMP-mediated collagen turnover were able to differentiate ovarian and breast cancer patients from healthy controls.Keywords: Cancer, extracellular matrix, collagen, biomarkers, breast cancer, ovarian cancer, matrix metalloproteinase, degradation, remodeling, tumor microenvironment BackgroundWomen's health is significantly influenced by the occurrence of cancers, such as breast and ovarian can- cers. Breast cancer is the leading cause of cancer death among women in the US and EU [1,2], and ovarian cancer, although less frequent, is often discovered in the late clinical stages where the cancer has already spread and no curative interventions are possible [3]. Taken together, the medical needs for breast and ovarian cancer are early diagnosis, prognosis and prediction of a therapeutic response. One of the best ways to achieve this is to use serum biomarkers [4].

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“…MMP‐degraded type III collagen (C3M)9 and formation of type III collagen (Pro‐C326) were examined. Additionally, MMP‐degraded type I (C1M) and type IV (C4M) collagen were measured 10.…”

Section: Methodsmentioning

confidence: 99%

“…They can be measured with protein fingerprint technology using specific antibodies 7. The levels of these ECM markers depend on the degree of fibrosis4, 8, 9, 10 and also reflect antifibrotic therapy 5, 11. Degradation markers and collagen type III formation, in particular, mirror progression of fibrosis and diagnosis of portal hypertension4, 10, 12, 13; however, the roles of these markers in decompensation of liver cirrhosis have not been assessed.…”

Section: Introductionmentioning

confidence: 99%

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

Praktiknjo

Lehmann

Nielsen

et al. 2018

Hepatology Communications

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Patients with end‐stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute‐on‐chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III plays a role in the acceleration of liver cirrhosis after AD and analyzed its formation (Pro‐C3) and degradation (matrix metalloproteinase‐degraded type III collagen [C3M]) markers in animal models and human disease. Bile duct ligation induced different stages of liver fibrosis in rats. Fibrosis development (hydroxyprolin content, sirius red staining, α‐smooth muscle actin immunohistochemistry, messenger RNA of profibrotic cytokines), necroinflammation (aminotransferases levels), fibrolysis (matrix metalloproteinase 2 expression and activity, C1M, C4M), and Pro‐C3 and C3M were analyzed 2, 3, 4, 5, and 6 weeks after bile duct ligation (n = 5 each group). In 110 patients with decompensated liver cirrhosis who underwent a transjugular intrahepatic portosystemic shunt procedure for AD, clinical and laboratory parameters as well as Pro‐C3 and C3M were measured in blood samples from portal and hepatic veins and were collected just before the transjugular intrahepatic portosystemic shunt placement and 1‐3 weeks later. Animal studies showed increased markers of collagen type III deposition with fibrosis, necroinflammation, and decompensation of liver cirrhosis, defined as ascites development. Higher Pro‐C3 levels were associated with injury, disease severity scores (Model for End‐Stage Liver Disease, Child‐Pugh, chronic liver failure‐C AD), ACLF development, and mortality. C3M decreased with AD and the chronic liver failure‐C AD score. Collagen type III deposition ratio increased with the risk of ACLF development and mortality. Conclusion: We show for the first time that AD boosts collagen type III deposition in experimental and human cirrhosis, possibly contributing to the worsened outcome in patients with decompensated cirrhosis. (Hepatology Communications 2018;2:211–222)

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Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis

Cited by 103 publications

References 33 publications

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

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