Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue Diseases<i>Possibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure</i>

Karsdal, Morten A.; Nielsen, Mette Juul; Sand, J.M.B.; Henriksen, Kim; Genovese, Federica; Bay‐Jensen, Anne‐Christine; Smith, Victoria; Adamkewicz, Joanne I.; Christiansen, Claus; Leeming, Diana Julie

doi:10.1089/adt.2012.474

Cited by 232 publications

(218 citation statements)

References 372 publications

(352 reference statements)

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“…Enzymatic cross-linking is typically mediated by the lysyl oxidase family of enzymes and/or by tissue transglutaminase, whereas nonenzymatic reactions, such as isomerization, glycosylation, and sulfation, occur either spontaneously or in response to increased blood glucose levels (as in the case of advanced glycation end products) (28). These various post-translational modifications can result in significant stiffening of ECM and resultant pathology when normal remodeling functions are subverted.…”

Section: Modulation Of Ecm Stiffnessmentioning

confidence: 99%

Lung Extracellular Matrix and Fibroblast Function

2015

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Extracellular matrix (ECM) is a tissue-specific macromolecular structure that provides physical support to tissues and is essential for normal organ function. In the lung, ECM plays an active role in shaping cell behavior both in health and disease by virtue of the contextual clues it imparts to cells. Qualities including dimensionality, molecular composition, and intrinsic stiffness all promote normal function of the lung ECM. Alterations in composition and/or modulation of stiffness of the focally injured or diseased lung ECM microenvironment plays a part in reparative processes performed by fibroblasts. Under conditions of remodeling or in disease states, inhomogeneous stiffening (or softening) of the pathologic ECM may both precede modifications in cell behavior and be a result of disease progression. The ability of ECM to stimulate further ECM production by fibroblasts and drive disease progression has potentially significant implications for mesenchymal stromal cell-based therapies; in the setting of pathologic ECM stiffness or composition, the therapeutic intent of progenitor cells may be subverted. Taken together, current data suggest that lung ECM actively contributes to health and disease; thus, mediators of cell-ECM signaling or factors that influence ECM stiffness may represent viable therapeutic targets in many lung disorders.

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Section: Modulation Of Ecm Stiffnessmentioning

confidence: 99%

Lung Extracellular Matrix and Fibroblast Function

2015

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“…During ECM remodeling, matrix metalloproteinases (MMPs) generate small peptide fragments, known as neoepitopes, that are released into the circulation. 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.…”

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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“…Because PHC in RA provides a sizeable clinical and economic drive for innovation, the prospect to address this interference now exists through a range of emerging diagnostic technologies that can be applied to everyday clinical practice, as developments in clinical chemistry are driven by enhanced technological understanding and the measurement of specific analytes with a high information content (33,34). For example, a new type of molecular marker has been developed that can quantify the levels of tissue destruction associated with a progressing pathology (35,36). In contrast to total protein measurement of established inflammatory biomarkers, such as IL-1, IL-6, and C-reactive protein, the markers are the consequence of protein degradation and tissue destruction and are released into the serum where they may be quantified as more tissuespecific makers of pathology.…”

Section: Significance and Innovationsmentioning

confidence: 99%

“…In contrast to total protein measurement of established inflammatory biomarkers, such as IL-1, IL-6, and C-reactive protein, the markers are the consequence of protein degradation and tissue destruction and are released into the serum where they may be quantified as more tissuespecific makers of pathology. These fragments are referred to as protein fingerprints (33,36) and represent a characteristic and reproducible end point of a specific pathologic process. Some of the major extracellular (ECM) constituents of the tissues in the joint are type I, II, and III collagen (37) that are degraded in the rheumatic pathologies, resulting in the release of protein fingerprints.…”

Section: Significance and Innovationsmentioning

confidence: 99%