Publications - Extracellular Matrix Research

Hyperpolarized [1- 13 C] Alanine Production: A Novel Imaging Biomarker of Renal Fibrosis

Purpose: Renal tubulointerstitial fibrosis is strongly linked to the progressive decline of renal function seen in chronic kidney disease. State-of-the-art noninvasive diagnostic modalities are currently unable to detect the earliest changes associated with the onset of fibrosis. This study was unde…

Osteoarthritis: Current Molecular Biomarkers and the Way Forward

The ultimate hope of researchers and patients is a pathway to development of treatments for osteoarthritis to modify the disease process in addition to the symptoms. However, development of disease modifying drugs requires objective endpoints such as measures of joint structure, joint tissue homeost…

Exploring the Role of Extracellular Matrix Proteins to Develop Biomarkers of Plaque Vulnerability and Outcome

Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the ar…

Type III, IV, and VI Collagens Turnover in Systemic Sclerosis - A Longitudinal Study

Tissue turnover, especially in the skin, is altered in systemic sclerosis (SSc), leading to tissue accumulation. The objective was to examine type III, IV, and VI collagens turnovers in SSc and investigate longitudinal alterations in relation to modified Rodnan Skin Score (mRSS). We included patient…

Correlation Between Serological Biomarkers of Extracellular Matrix Turnover and Lung Fibrosis and Pulmonary Artery Hypertension in Patients With Systemic Sclerosis

Objective: To determine the value of serological biomarkers of collagen degradation/turnover as serum markers of organ involvement in patients with systemic sclerosis (SSc).

Methods: Serum samples were obtained from 79 SSc patients and 19 healthy control subjects. Types I to VI collagen turnover,…

Collagen Biology and Non-Invasive Biomarkers of Liver Fibrosis

There is an unmet need for high-quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non-alcoholic fatty liv…

Sprifermin (rhFGF18) Versus Vehicle Induces a Biphasic Process of Extracellular Matrix Remodeling in Human Knee OA Articular Cartilage Ex Vivo

Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characteriz…

A Fragment of Collagen Type VI alpha-3 Chain Is Elevated in Serum From Patients With Gastrointestinal Disorders

Extracellular matrix (ECM) remodeling is a hallmark of the pathology of gastrointestinal disorders. Collagen type VI (COL6) is produced by fibroblasts, and the COL6 α3-chain has shown to be elevated in patients with ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC). Measuring…

Atrial Fibrillation and Cardiac Fibrosis: A Review on the Potential of Extracellular Matrix Proteins as Biomarkers

The involvement of fibrosis as an underlying pathology in heart diseases is becoming increasingly clear. In recent years, fibrosis has been granted a causative role in heart diseases and is now emerging as a major contributor to Atrial Fibrillation (AF) pathogenesis. AF is the most common arrhythmia…

Increased Von Willebrand Factor Processing in COPD, Reflecting Lung Epithelium Damage, Is Associated With Emphysema, Exacerbations and Elevated Mortality Risk

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and lung tissue deterioration. Given the high vascularity of the lung, von Willebrand factor (VWF), a central component of wound healing initiation, has previously been assessed in COPD. VWF processing,…

Lost in transition: biomarkers of remodeling in patients with asthma.

PURPOSE OF REVIEW:
'Biomarkers of remodeling' represent a loose collection of features referring to several biological adaptations of the lung to cope with stressing factors. In addition, remodel-'ing' infers a dynamic process that would require a spatiotemporal resolution. This review focuses on d…

Imbalanced turnover of collagen type III is associated with disease progression and mortality in high-risk chronic kidney disease patients

Background
Tubulointerstitial fibrosis is a major pathological feature in chronic kidney disease (CKD) and collagen type III (COL3) is a major component of the renal fibrotic scar. We hypothesized that a dysregulated turnover of COL3 is an important determinant of CKD progression. We assessed the r…

Cirrhotic Human Liver Extracellular Matrix 3D Scaffolds Promote Smad-Dependent TGF-β1 Epithelial Mesenchymal Transition.

An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify …

Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular …

Is the Total Amount as Important as Localization and Type of Collagen in Liver Fibrosis Attributable to Steatohepatitis?

Is liver fibrosis just liver fibrosis? Or do the subtype of collagen, its spatial localization in the liver, its cell of origin, and the time point at which it is synthesized also matter? It is important, since the various collagen subtypes hold different informative values regarding reparative proc…

End-product of fibrinogen is elevated in emphysematous chronic obstructive pulmonary disease and is predictive of mortality in the ECLIPSE cohort.

BACKGROUND:
Chronic obstructive pulmonary disease (COPD) is characterized by abnormal epithelial repair process that may result in intra-airway accumulation of fibrin. Given that plasma fibrinogen is the only FDA approved biomarker that predicts mortality and COPD exacerbations, we hypothesized tha…

Post-translational modifications of vimentin reflect different pathological processes associated with non-small cell lung cancer and chronic obstructive pulmonary disease.

Vimentin has shown to be highly implicated in cancer initiation and progression. Vimentin is often a target of post-translational modifications (PTMs) which can be disease specific, thus targeting these specific modifications can be of high biomarker potential. In this study we set out to evaluate t…

Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors.

OBJECTIVE:
Links between pain and joint degradation are poorly understood. We investigated the role of activation of Toll-like receptors (TLR) by cartilage metabolites in initiating and maintaining the inflammatory loop in OA causing joint destruction.

METHODS:
Synovial membrane explants (SMEs)…

Collagen turnover profiles in chronic kidney disease.

Renal fibrosis is a hallmark of chronic kidney disease (CKD) caused by an imbalance between formation and degradation of extracellular matrix proteins. We investigated the collagen turnover profile of 81 non-dialysis CKD stage 2-5 patients by measuring peptides reflecting formation and degradation o…

An Ex Vivo Tissue Culture Model of Cartilage Remodeling in Bovine Knee Explants.

Ex vivo culture systems cover a broad range of experiments dedicated to studying tissue and cellular function in a native setting. Cartilage is a unique tissue important for proper function of the synovial joint and is constituted by a dense extracellular matrix (ECM), rich in proteoglycan and type …

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer.

Hyaluronan (HA) and collagen are highly expressed in pancreatic cancer (PC) stroma. HA and collagen accumulation increase tumor interstitial fluid pressure, compromising blood flow and drug penetration. The aim of this biomarker study was to determine the clinical utility of serum HA and the propept…

The intestinal tissue homeostasis - the role of extracellular matrix remodeling in inflammatory bowel disease

Introduction: Extracellular matrix (ECM) remodeling of the intestinal tissue is important in inflammatory bowel disease (IBD) due to the extensive mucosal remodeling. There are still gaps in our knowledge as to how ECM remodeling is related to intestinal epithelium homeostasis and healing of the int…

Serum markers of type III and IV procollagen processing predict recurrence of fibrosis in liver transplanted patients.

Following liver transplantation (LT), 10-30% of patients develop recurrent cirrhosis (RC). There is an urgent need for predictive non-invasive markers for improved monitoring of these patients. Here we studied extracellular matrix biomarkers as predictors of RC after LT. Forty-seven LT patients were…

Biochemical markers in osteoarthritis with lessons learned from osteoporosis.

Osteoarthritis (OA) is a disease of the whole joint, including synovium, bone and cartilage. OA is a slow degenerative and very heterogeneous disease, with both varying levels of disease activity and progression. Biomarkers are urgently needed to assist drug developers in selecting and developing th…

Associations between biomarkers of bone and cartilage turnover, gender, pain categories and radiographic severity in knee osteoarthritis.

BACKGROUND:
Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee j…

Clinical Relevance of Collagen Protein Degradation Markers C3M and C4M in the Serum of Breast Cancer Patients Treated with Neoadjuvant Therapy in the GeparQuinto Trial.

Background: Remodeling of extracellular matrix through collagen degradation is a crucial step in the metastatic cascade. The aim of this study was to evaluate the potential clinical relevance of the serum collagen degradation markers (CDM) C3M and C4M during neoadjuvant chemotherapy for breast cance…

Metabolites of type I, II, III, and IV collagen may serve as markers of disease activity in axial spondyloarthritis.

Local inflammation in axial spondyloarthritis (axSpA) leads to the release of collagen metabolites from the disease-affected tissue. We investigated whether collagen metabolites were associated with disease activity and could distinguish non-radiographic(nr)-axSpA from ankylosing spondylitis (AS). A…

Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort.

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was ass…

Circulating levels of PRO-C3 reflect liver fibrosis and liver function in HIV positive patients receiving modern cART

Abstract
Background and aims
Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recen…

Performance of the PRO-C3 collagen neo-epitope biomarker in non-alcoholic fatty liver disease.

There is an unmet need for non-invasive biomarkers in non-alcoholic fatty liver disease (NAFLD) that can diagnose advanced disease and identify patients suitable for clinical trials. The PRO-C3 collagen neo-epitope is a putative direct marker of fibrogenesis. We assessed the performance of PRO-C3 in…

Serological Assessment of Activated Fibroblasts by alpha-Smooth Muscle Actin (α-SMA): A Noninvasive Biomarker of Activated Fibroblasts in Lung Disorders

OBJECTIVES:
Remodeling of the extracellular matrix (ECM) is a key event in different lung disorders, such as fibrosis and cancer. The most common cell type in the connective tissue is fibroblasts, which transdifferentiate into myofibroblasts upon activation. All myofibroblasts express α-SMA, which …

Collagen type IV remodelling gender-specifically predicts mortality in decompensated cirrhosis

BACKGROUND & AIMS:
Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute decompensation. Extratracellular matrix is compiled of deposition of various components. The role of basement membrane collagen type IV in advanced …

The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.

Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluatio…

Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.

A non-invasive biomarker of type III collagen degradation reflects ischaemia reperfusion injury in rats.

BACKGROUND:
Maintenance of kidney function in kidney allografts remains a challenge, as the allograft often progressively develops fibrosis after kidney transplantation. Fibrosis is caused by the accumulation of extracellular matrix proteins like type I and III collagen (COL I and III) that replace…

Serum biomarkers of collagen turnover as potential diagnostic tools in diffuse systemic sclerosis: A cross-sectional study

BACKGROUND:
Systemic sclerosis (SSc) is characterized by excessive fibrosis throughout the body. This leads to the release of extracellular matrix (ECM) fragments into circulation, where they may be quantified as biomarkers. The objectives were to investigate levels of ECM turnover biomarkers and t…

Citrullinated Vimentin and biglycan protein fingerprints as candidate serological biomarkers for disease activity in systemic sclerosis: A pilot study.

PURPOSE:
Extracellular matrix (ECM) deposition and remodelling in skin and lungs of systemic sclerosis (SSc) subjects lead to release of metabolites/biomarkers into circulation. We investigated if biomarkers of ECM degradation (biglycan and elastin) and macrophage activation (citrullinated vimentin…

Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction.

BACKGROUND:
Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling.

METHODS AND RESULTS:
Patients with acute MI had higher plasma CatK lev…

Alterations in non-type I collagen biomarkers in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a rare disorder of connective tissue caused by abnormalities in the synthesis or processing of type I collagen. Type I collagen is the most abundant type of collagen and is expressed in almost all connective tissues. Given that type I collagen interacts with other col…

A novel biomarker of laminin turnover is associated with disease progression and mortality in chronic kidney disease.

BACKGROUND:
Patients with chronic kidney disease (CKD) have increased risk of development of end-stage renal disease (ESRD) and early mortality. Fibrosis is the central pathogenic process in CKD and is caused by dysregulated extracellular matrix (ECM) remodeling. The laminin γ1 chain (LAMC1) is a c…

A biomarker of collagen type I degradation is associated with cardiovascular events and mortality in patients with atherosclerosis.

OBJECTIVE:
Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix (ECM) proteins in the arterial wall. Collagen type I (COL1), a component of the arterial ECM, is cleaved by matrix metalloproteinases (MMPs) and known to be remodelled in atherosclerosis. We explor…

Bone and soft tissue turnover in relation to all-cause mortality in postmenopausal women.

BACKGROUND:
The relationship between levels of extracellular matrix (ECM) turnover and mortality is currently unknown. The study aimed to determine if levels of ECM turnover are predictors of all-cause mortality in a large cohort of post-menopausal women.

METHODS:
5,855 postmenopausal Danish wo…

A Serological Biomarker of Versican Degradation is Associated with Mortality Following Acute Exacerbations of Idiopathic Interstitial Pneumonia

BACKGROUND:
Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis. Acute exacerbations of IIP represent periods of increased disease activity, thus we hypothesized that ECM remodeling was altered during acute exa…

Aggrecanase degradation of type III collagen is associated with clinical knee pain

There is a lack of biochemical markers for non-invasive and objective assessment of symptomatic osteoarthritis (OA). Aggrecanase activity has been shown to be associated with joint deterioration and symptomatic disease through the degradation of extracellular matrix proteins, such as type III collag…

Mass spectrometry-based identification of cross-links in proteins exposed to photo-oxidation and peroxyl radicals using 18/O labeling and optimized MS/MS fragmentation

Protein cross-links are formed in regulated biochemical processes in many biological systems, but they are also generated inadvertently via the reactions of exogenous or endogenous oxidants. Site-specific identification and characterization of such cross-links is challenging and the goal was therefo…

Higher collagen VI formation is associated with all-cause mortality in type 2 diabetic patients with microalbuminuria

OBJECTIVE:
Type 2 diabetes is a common risk factor for the development of chronic kidney disease (CKD). Enhanced de novo collagen type VI (COL VI) formation has been associated with renal fibrosis and CKD. We investigated the hypothesis that PRO-C6, a product specifically generated during COL VI fo…

Osteoclasts degrade bone and cartilage knee joint compartments through different resorption processes

BACKGROUND:
Osteoclasts have been strongly implicated in osteoarthritic cartilage degradation, at least indirectly via bone resorption, and have been shown to degrade cartilage in vitro. The osteoclast resorption processes required to degrade subchondral bone and cartilage-the remodeling of which i…

Type V collagen is persistently altered after inguinal hernia repair

BACKGROUND AND AIMS:
Hernia formation is associated with alterations of collagen metabolism. Collagen synthesis and degradation cause a systemic release of products, which are measurable in serum. Recently, we reported changes in type V and IV collagen metabolisms in patients with inguinal and inci…

Assessment of extracellular matrix-related biomarkers in patients with lower extremity artery disease

BACKGROUND:
The prevalence of lower extremity artery disease (LEAD) is high (20%-25%) in the population older than 65 years, but patients are seldom identified until the disease is advanced. Circulating markers of disease activity might provide patients with a key opportunity for timely treatment. …

Age-related collagen turnover of the interstitial matrix and basement membrane: Implications of age- and sex-dependent remodeling of the extracellular matrix

The extracellular matrix (ECM) plays a vital role in maintaining normal tissue function. Collagens are major components of the ECM and there is a tight equilibrium between degradation and formation of these proteins ensuring tissue health and homeostasis. As a consequence of tissue turnover, small c…

Matrix Metalloproteinase Mediated Type I Collagen Degradation is an Independent Predictor of Increased Risk of Acute Myocardial Infarction in Postmenopausal Women

Chronic fibro-proliferative diseases are associated with nearly 45% of all deaths in the developed world. Matrix metalloproteinase (MMP) mediated remodeling of the extracellular matrix (ECM) plays an important role in disease development. Degradation of type I collagen is considered having a major r…

Tumstatin, a Matrikine Derived from Collagen Type IVα3, is Elevated in Serum from Patients with Non-Small Cell Lung Cancer

OBJECTIVES
Fibrosis and cancer are characterized by extracellular matrix (ECM) remodeling. The basement membrane is mainly composed by collagen type IV and laminin. Tumstatin is a matrix metalloproteinase-9 (MMP-9) generated matrikine of collagen type IV α3 chain. We evaluated the potential of tums…

Development of a Neo-Epitope Specific Assay for Serological Assessment of Type VII Collagen Turnover and Its Relevance in Fibroproliferative Disorders

Type VII collagen is the main component of the anchoring fibrils connecting the basement membrane to the underlying interstitial matrix. Mutations in the type VII collagen gene cause dystrophic epidermolysis bullosa. Increased levels of type VII collagen in the skin have been reported in patients wi…

Accelerated collagen turnover in women with angina pectoris without obstructive coronary artery disease: An iPOWER substudy

AIM:
Collagens are major cardiac extracellular matrix components, known to be actively remodelled and accumulated during diffuse myocardial fibrosis. We evaluated whether accelerated collagen turnover described by neo-epitope biomarkers reflecting collagen formation and degradation separates patie…

Understanding Cardiac Extracellular Matrix Remodeling to Develop Biomarkers of Myocardial Infarction Outcomes

Cardiovascular Disease (CVD) is the most common cause of death in industrialized countries, and myocardial infarction (MI) is a major CVD with significant morbidity and mortality. Following MI, the left ventricle (LV) undergoes a wound healing response to ischemia that results in extracellular matri…

Objective Cognitive Impairment and Progression to Dementia in Women: The Prospective Epidemiological Risk Factor Study.

BACKGROUND:
Identification of subjects with a progressive disease phenotype is an urgent need in the pharmaceutical industry where most of the recent clinical trials in Alzheimer's disease have failed.

OBJECTIVES:
The objective of this study was to identify subgroups of individuals with objecti…

Inducible knockdown of procollagen I protects mice from liver fibrosis and leads to dysregulated matrix genes and attenuated inflammation

Organ fibrosis is characterized by a chronic wound-healing response, with excess deposition of extracellular matrix components. Here, collagen type I represents the most abundant scar component and a primary target for antifibrotic therapies. Liver fibrosis can progress to cirrhosis and primary live…

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 pr…

Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities

Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a n…

Changes of patient-reported outcomes and protein fingerprint biomarkers after exercise therapy for axial spondyloarthritis

The objective of this study was to investigate the patient-reported outcomes (PROs) and matrix metalloproteinase (MMP) derived extracellular matrix (ECM) biomarkers in non-radiographic (nr)-axial spondyloarthritis (axSpA) and radiographic (r)-axSpA after exercise intervention. Forty-six axSpA patien…

Non-invasive evaluation of extracellular matrix remodeling in peripheral artery disease

AIM:
Peripheral artery disease (PAD) is a common manifestation of systemic atherosclerosis affecting peripheral arteries. The underlying pathology of PAD are disorganized extracellular matrix (ECM), caused by inflammation and oxidation. Previous studies have demonstrated an important structure dis…

The good and the bad collagens of fibrosis - Their role in signaling and organ function

Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or…

Modifiable risk factors promoting neurodegeneration is associated with two novel brain degradation markers measured in serum

There has been limited success with blood-based biomarkers of neurodegeneration. One perceived reason is that blood has no direct contact to the brain. Recently developed blood-based biomarkers of tau-degradation have shown promise as potential tools for peripheral assessment of neurodegeneration; h…

Biomarker of extracellular matrix remodelling C1M and proinflammatory cytokine IL-6 are related to synovitis and pain in endstage knee osteoarthritis patients

Little is known about local and systemic biomarkers in relation to synovitis and pain in end-stage osteoarthritis (OA) patients. We investigated the associations between the novel extracellular matrix biomarker, C1M, and local and systemic interleukin 6 (IL-6) with synovitis and pain. Serum C1M, pla…

Chondrocyte secretome: a source of novel insights and exploratory biomarkers of osteoarthritis

The extracellular matrix (ECM) of articular cartilage is comprised of complex networks of proteins and glycoproteins, all of which are expressed by its resident cell, the chondrocyte. Cartilage is a unique tissue given its complexity and ability to resist repeated load and deformation. The mechanism…

The minor collagens in articular cartilage

Articular cartilage is a connective tissue consisting of a specialized extracellular matrix (ECM) that dominates the bulk of its wet and dry weight. Type II collagen and aggrecan are the main ECM proteins in cartilage. However, little attention has been paid to less abundant molecular components, es…

Excessive matrix metalloprotease-mediated degradation of interstitial tissue (type I collagen) independently predicts short-term survival in an observational study of postmenopausal women diagnosed with cancer

Extensive tissue remodeling mediated by matrix metalloproteases (MMPs) is an important part of cancer. The aim of this study was to investigate whether serum biomarkers reflecting MMP-mediated degradation of type I collagen (C1M), type IV collagen (C4M) and citrullinated vimentin (VICM) were predict…

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

BACKGROUND:
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM). Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elas…

High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD - results from the ECLIPSE study

BACKGROUND:
There is a need to identify individuals with COPD at risk for disease progression and mortality. Lung tissue remodeling is associated with the release of extracellular matrix (ECM) fragments into the peripheral circulation. We hypothesized that ECM remodeling was associated with mortali…

Fibrosis is not just fibrosis - basement membrane modelling and collagen metabolism differs between hepatitis B- and C-induced injury

BACKGROUND:
While morphological patterns differ, the molecular phenotype of liver fibrosis is considered a stereotypical response to chronic liver injury. However, with different cellular triggers and networks regulating fibrosis, the molecular responses of the injured liver may not be identical.
…

Type VIII collagen is elevated in diseases associated with angiogenesis and vascular remodeling

OBJECTIVES:
Type VIII collagen is involved in angiogenesis and remodeling of arteries. We hypothesized that type VIII collagen was upregulated in diseases associated with vascular remodeling, e.g. pulmonary fibrosis and cancer. In this paper we present the development and validation of a competiti…

Quantification of fibronectin as a method to assess ex vivo extracellular matrix remodeling

Altered architecture, composition and quality of the extracellular matrix (ECM) are pathological hallmarks of several inflammatory and fibro-proliferative pathological processes such as osteoarthritis (OA), rheumatoid arthritis (RA), fibrosis and cancer. One of the most important components of the E…

Tissue turnover of collagen type I, III and elastin is elevated in the PCLS model of IPF and can be restored back to vehicle levels using a phosphodiesterase inhibitor

BACKGROUND:
The aim of this study was to develop and validate a model for pulmonary fibrosis, using ex vivo tissue cultures of lungs from bleomycin treated animals, enabling the investigation of fibrosis remodeling using novel biomarkers for the detection of ECM protein fragments. The combination …

Precision-Cut Kidney Slices as a Tool to Understand the Dynamics of Extracellular Matrix Remodeling in Renal Fibrosis

The aim of this study was to set up an ex vivo model for renal interstitial fibrosis in order to investigate the extracellular matrix (ECM) turnover profile in the fibrotic kidney. We induced kidney fibrosis in fourteen 12-week-old male Sprague Dawley rats by unilateral ureteral obstruction (UUO) su…

Synovitis biomarkers: ex vivo characterization of three biomarkers for identification of inflammatory osteoarthritis

OBJECTIVE:
Characterize biomarkers measuring extracellular matrix turnover of inflamed osteoarthritis synovium.

METHODS:
Human primary fibroblast-like synoviocytes and synovial membrane explants (SMEs) treated with various cytokines and growth factors were assessed by C1M, C3M, and acMMP3 in …

Protein degradation fragments as diagnostic and prognostic biomarkers of connective tissue diseases: understanding the extracellular matrix message and implication for current and future serological biomarkers

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 pat…

Collagen and tissue turnover as function of age - implications for fibrosis

BACKGROUND:
The extracellular matrix (ECM) is the backbone of all tissues. It is a complex grid consisting of multiple structural proteins which each play a vital role for the function and maintenance of normal tissue function. In development and growth, tissue is being formed and elaborated (tissu…

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

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…

Matrix Metalloproteinase Mediated Type I Collagen Degradation - An Independent Risk Factor for Mortality in Women

Chronic fibro-proliferative diseases are associated with nearly 45% of all deaths in the developed world. Matrix metalloproteinase (MMP) mediated remodeling of the extracellular matrix (ECM) plays an important role in disease development. Degradation of type I collagen is considered having a major r…

Turnover of type III collagen reflects disease severity and is associated with progression and microinflammation in patients with IgA nephropathy

BACKGROUND:
Renal fibrosis is the hallmark of progression to end-stage kidney disease. Non-invasive biomarkers of renal fibrosis could serve as specific end points in clinical trials and improve monitoring and stratification of patients with chronic kidney disease (CKD). To address this, we measure…

The importance of extracellular matrix for cell function and in vivo likeness

OBJECTIVE:
Fibrotic diseases may be described as a disease of the extracellular matrix, where the balance between matrix formation and degradation has been shifted leading to an accumulation of matrix. Currently a fit for purpose model and readily available approach are adapted when doing cell cult…

Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C

BACKGROUND & AIMS:
Fibrogenesis results in release of certain extracellular matrix protein fragments into the circulation. We evaluated the diagnostic and prognostic performance of two novel serological markers, the precisely cleaved N-terminal propeptide of type III collagen (Pro-C3) and a peptide…

Association of versican turnover with all-cause mortality in patients on haemodialysis

OBJECTIVE:
Cardiovascular diseases are among the most common causes of mortality in renal failure patients undergoing haemodialysis. A high turnover rate of the proteoglycan versican, represented by the increased presence of its fragmentation products in plasma, has previously been associated with …

The role of extracellular matrix quality in pulmonary fibrosis

This review discusses the role of extracellular matrix (ECM) quality in the pathogenesis of pulmonary fibrosis (PF). In PF, the highly ordered structure of collagens and elastin within the ECM of the lung is severely disrupted and lacks its original tissue quality. Discussions about the ECM have foc…

Measurement of a MMP-2 degraded Titin fragment in serum reflects changes in muscle turnover induced by atrophy

PURPOSE:
In this study we sought to determine whether a Titin peptide fragment can serve as a clinical biomarker for changes in muscle mass.

METHODS:
Mass spectrometry was used to identify Titin fragment in urine. An antibody against this Titin sequence was raised and used to develop a competit…

Type X collagen levels are elevated in serum from human osteoarthritis patients and associated with biomarkers of cartilage degradation and inflammation

BACKGROUND:
Osteoarthritis (OA) is the most common degenerative joint disease, of which the pathogenesis is inadequately understood. Hypertrophy-like changes have been observed as part of the progression of OA. The aim of the study was to develop and characterize a novel biomarker of chondrocytes h…

Review article: the efficacy of biomarkers in chronic fibroproliferative diseases - early diagnosis and prognosis, with liver fibrosis as an exemplar

BACKGROUND:
Nearly 45% of all deaths are associated with chronic fibroproliferative diseases, of which the primary characteristic is altered remodelling of the extracellular matrix. A major difficulty in developing anti-fibrotic therapies is the lack of accurate and established techniques to estima…

The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?

Interstitial fibrosis is the common endpoint of end-stage chronic kidney disease (CKD) leading to kidney failure. The clinical course of many renal diseases, and thereby of CKD, is highly variable. One of the major challenges in deciding which treatment approach is best suited for a patient but also…

Quantification of "end products" of tissue destruction in inflammation may reflect convergence of cytokine and signaling pathways -- implications for modern clinical chemistry

The degree of inflammation in auto-immune diseases such as rheumatoid arthritis is often assessed in serum and used for diagnostic and prognostic purposes. The serum levels of acute inflammatory signaling molecules (C-reactive protein and serum amyloid A) in conjunction with the important pro-inflam…

A MMP derived versican neo-epitope is elevated in plasma from patients with atherosclerotic heart disease

Extracellular matrix remodelling is a prerequisite for plaque rupture in atherosclerotic lesion. Versican, an extracellular matrix proteoglycan present in normal and atherosclerotic arteries is a substrate for matrix metalloproteinases (MMPs) present in macrophage rich areas. The aim of the current …

Biglycan fragmentation in pathologies associated with extracellular matrix remodeling by matrix metalloproteinases

BACKGROUND:
The proteoglycan biglycan (BGN) is involved in collagen fibril assembly and its fragmentation is likely to be associated with collagen turnover during the pathogenesis of diseases which involve dysregulated extracellular matrix remodeling (ECMR), such as rheumatoid arthritis (RA) and li…

Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure

Increased attention is paid to the structural components of tissues. These components are mostly collagens and various proteoglycans. Emerging evidence suggests that altered components and noncoded modifications of the matrix may be both initiators and drivers of disease, exemplified by excessive ti…

Clinical evaluation of a matrix metalloproteinase-12 cleaved fragment of titin as a cardiovascular serological biomarker

BACKGROUND:
Titin is a muscle-specific protein found in cardiac and skeletal muscles which is responsible for restoring passive tension. Levels and functioning of titin have been shown to be affected by cardiac damage. Due to the inherent difficulty of measuring titin levels in vivo in a clinical s…

Molecular serum markers of liver fibrosis

Fibrosis is a hallmark histologic event of chronic liver diseases and is characterized by the excessive accumulation and reorganization of the extracellular matrix (ECM). The gold standard for assessment of fibrosis is liver biopsy. As this procedure has various limitations, including risk of patien…

Protein fingerprints - relying on and understanding the information of serological protein measurements

In 2004, the FDA has articulated a Critical Path Initiative to improve the efficiency of product development industry-wide, and brought attention to the pressing needs of defining new tools to better assess safety and effectiveness of new products. A better understanding of protein subtypes, protein…

Serological biochemical markers of surrogate efficacy and safety as a novel approach to drug repositioning

How do pharmaceutical companies find new uses for old or failed drugs? Is there a way to 'manage serendipity' at the very first stage of identifying compounds that could be developed into new drugs? Several approaches are now being pursued by various companies that are dedicated to drug repositionin…

Post-translational modifications of the extracellular matrix are key events in cancer progression: opportunities for biochemical marker development

The aim of this review is to discuss the potential usefulness of a novel class of biochemical markers, designated neoepitopes. Neoepitopes are post-translational modifications (PTMs) of proteins and are derived by processes, such as protease cleavage, citrullination, nitrosylation, glycosylation and…

Novel combinations of Post-Translational Modification (PTM) neo-epitopes provide tissue-specific biochemical markers--are they the cause or the consequence of the disease?

The aim of this review is to discuss the potential usefulness of novel advances in the class of biochemical markers, neo-epitopes. Neo-epitopes are post-translational modifications (PTMs) of proteins formed by processes such as protease cleavage, citrullination, nitrosylation, glycosylation and isom…

Serum markers of liver fibrosis: combining the BIPED classification and the neo-epitope approach in the development of new biomarkers

BACKGROUND:
Fibrosis is a central histological feature of chronic liver diseases and is characterized by the accumulation and reorganization of the extracellular matrix. The gold standard for assessment of fibrosis is histological evaluation of a percutaneous liver biopsy. Albeit a considerable eff…

Biochemical markers and the FDA Critical Path: how biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development

The aim of this review is to discuss the potential usefulness of a novel class of biochemical markers, neoepitopes, in the context of the US Food and Drug Administration (FDA) Critical Path Initiative, which emphasizes biomarkers of safety and efficacy as areas of pivotal interest. Examples of prote…