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The aim of this review is to discuss the potential usefulness of novel biochemical markers of connective tissues: neo-epitopes of extracellular matrix proteins generated by post-translational modifications by tissue proteinases. As each modification results from a specific local physiological or pathobiological process, the identification of specific proteinase-mediated cleavage products of tissue-specific proteins may produce a unique disease-specific biochemical marker. The authors present a novel interpretation of the process of tissue degradation described by neo-epitope fragments of the interstitial and basement membrane matrix in fibrotic disease, and the diagnostic and prognostic potential of such markers. Moreover, the authors highlight the importance of matrix protein fragments not only as markers of tissue remodeling, but also as players in tissue remodeling, due to their signaling properties. © 2016 Taylor & Francis.

Bay-Jensen A.C.,Cartilage Biology and Biomarkers | Leeming D.J.,Fibrosis Biology and Biomarkers | Kleyer A.,Friedrich - Alexander - University, Erlangen - Nuremberg | Veidal S.S.,Fibrosis Biology and Biomarkers | And 2 more authors.
Rheumatology International | Year: 2012

Ankylosing spondylitis (AS) is characterized by gradual cementation of the vertebrae, a process that is described by excessive extracellular matrix remodeling. Specific matrix metalloproteinase (MMP)-derived collagen fragments are released to the circulation, and measurement of those might act as biomarkers of ankylosis. The aim of the study was to investigate the diagnostic value of five novel assays measuring different collagen species. Five newly developed ELISAs measuring MMP-degraded collagen fragments in serum of 40 AS patients and 40 agematched controls were measured: collagen type I (C1M), type II (C2M), type III (C3M), type IV (C4M) and type VI (C6M) as well as the bone formation marker osteocalcin. The levels of the five collagen neoepitopes were significantly higher in AS patients, except for osteocalcin. Cartilage degradation (C2M) was only significantly correlated with the basement membrane (C4M) in the AS patients. In contrast, C3M was significantly correlated with all of the other collagen markers. The highest diagnostic value was achieved when combining the C2M, C3M and C6M markers, AUC 87% (P < 0.0001). Moreover, a combination of the markers correlated with the clinical mSASS score (P = 0.004, R = 0.44). Novel and unique biomarkers of tissue remodeling may provide diagnostic value and aid in understanding of the AS pathology. Each of the biomarkers tells a unique story, and by combining them in a panel there, we found a strong correlation with mSASSS. We speculate that such panel will be a valuable tool for monitoring patients as effect of treatment, for the prediction of responders and for diagnostic purposes. © Springer-Verlag 2011.

Sand J.M.,Fibrosis Biology and Biomarkers | Larsen L.,Fibrosis Biology and Biomarkers | Hogaboam C.,University of Michigan | Martinez F.,University of Michigan | And 6 more authors.
PLoS ONE | Year: 2013

Objectives: Fibrosis is characterized by excessive tissue remodeling resulting from altered expression of various growth factors, cytokines and proteases. We hypothesized that matrix metalloproteinase (MMP) mediated degradation of type IV collagen, a main component of the basement membrane, will release peptide fragments (neoepitopes) into the circulation. Here we present the development of two competitive enzyme-linked immunosorbent assays (ELISAs) for assessing the levels of specific fragments of type IV collagen α1 (C4M12a1) and α3 (C4M12a3) chains in serum as indicators of fibrosis. Methods: Fragments of type IV collagen cleaved in vitro by MMP-12 were identified by mass spectrometry, and two were chosen for ELISA development due to their unique sequences. The assays were evaluated using samples from a carbon tetrachloride (CCl4) rat model of liver fibrosis and from patients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD). Results: Two technically robust ELISAs were produced using neo-epitope specific monoclonal antibodies. Mean serum C4M12a1 levels were significantly elevated in CCl4-treated rats compared with controls in weeks 12, 16, and 20, with a maximum increase of 102% at week 16 (p < 0.0001). Further, C4M12a1 levels correlated with the total collagen content of the liver in CCl4-treated rats (r = 0.43, p = 0.003). Mean serum C4M12a3 levels were significantly elevated in patients with mild, moderate, and severe IPF, and COPD relative to healthy controls, with a maximum increase of 321% in COPD (p < 0.0001). Conclusions: Two assays measuring C4M12a1 and C4M12a3 enabled quantification of MMP mediated degradation of type IV collagen in serum. C4M12a1 was elevated in a pre-clinical model of liver fibrosis, and C4M12a3 was elevated in IPF and COPD patients. This suggests the use of these assays to investigate pathological remodeling of the basement membrane in different organs. However, validations in larger clinical settings are needed. © 2013 Sand et al.

Schierwagen R.,University of Bonn | Leeming D.J,Fibrosis Biology and Biomarkers | Klein S.,University of Bonn | Granzow M.,University of Bonn | And 6 more authors.
Frontiers in Physiology | Year: 2013

Background: Progression of liver fibrosis is characterized by synthesis and degradation of extracellular matrix (ECM). Matrix-metalloproteinases (MMP) cleave collagen fibers at a specific site and thereby generate soluble fragments of ECM (neo-epitopes). The levels of these neo-epitopes might reflect the stage of liver fibrosis and may allow monitoring of anti-fibrotic therapies. Here we analyzed these neo-epitopes as read-out for a liver directed therapy with statins. Methods: Bile duct ligation (BDL) was performed on wild type rats, which received atorvastatin (15 mg/kg*d) for 1 week starting at 1, 2, 3, 4 and 5 weeks after BDL (T1-T5), while controls remained untreated. Hepatic fibrosis was analyzed by immunohistochemistry and hepatic hydroxyproline content. TGFβ levels were measured by RT-PCR. Proteolytic activity of MMP-2 was examined by zymography. Levels of degradation MMP driven type I, III, IV and VI collagen degradation (C1M, C3M, C4M, and C6M) and type III and IV collagen formation (PRO-C3 and P4NP7S) markers were assessed by specific ELISAs in serum probes. Results: Serum markers of ECM neo-epitopes reflected significantly the deposition of ECM in the liver and were able to distinguish between early (T1-T3) and severe fibrosis (T4-T5). Statin treatment resulted in reduction of neo-epitope markers, especially when therapy was started in the stage of severe fibrosis (T4-T5). Furthermore, these markers correlated with hepatic expression of profibrotic cytokines TGFβ1 and TGFβ2. Formation markers of type III and IV collagen (PRO-C3 and P4NP7S) and degradation markers C4M and C6M correlated significantly with hepatic MMP-2 activity in rats with severe fibrosis. Conclusion: Determination of ECM remodeling turnover markers in serum allowed a distinction between mild and severe fibrosis. With respect to statin therapy, the markers may serve as read-out for efficacy of anti-fibrotic treatment.© 2013 Schierwagen, Leeming, Klein, Granzow, Nielsen, Sauerbruch, Krag, Karlsdal and Trebicka.

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