Type III and VI collagen remodeling biomarkers have the potential to distinguish between IPF and HP
Introduction
IPF and HP are two ILDs with similar clinical phenotype but distinct management, making their precise separation critical. Serological biomarkers may assist in this distinction. Extracellular matrix (ECM) remodeling is a hallmark of fibrosis. Collagen formation and degradation processes release peptide fragments into the blood that can be quantified by the nordicPRO-C3™ and nordicPRO-C6™ (type III and VI collagen formation), or the C3M and C6M (type III and VI collagen degradation) assays.
In this study we assessed the clinical value of Type III and VI collagen remodeling biomarkers and their potential to act as a tool to distinguish between HP and IPF in two separate, independent cohorts.
NordicPRO-C3™ and nordicPRO-C6™ fibrogenesis biomarkers in connective tissue disease-associated interstitial lung disease: results from the phase IIb RECITAL trial
Introduction
ILD is a major cause of morbidity and mortality in connective tissue disease (CTD). Cyclophosphamide is an effective treatment for CTD-ILD, but limited by side effects. In this study, we additionally tested rituximab as an alternative in the RECITAL phase IIb trial. Both drugs improved the lung function with rituximab showing fewer adverse events (Maher, 2022. Lancet Resp Med)
The decrease in nordicPRO-C3™ and nordicPRO-C6™ suggest that, besides their immunomodulatory effects, these drugs may also reduce fibrogenesis. Both biomarkers, measured at baseline and as % change from baseline, are associated with FVC response. These findings highlight nordicPRO-C3™ and nordicPRO-C6™ as promising biomarkers for progressive CTD-ILD.
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Identifying biomarkers of mild-stage emphysema in COPD patients via interpretable machine learning
Introduction
Emphysema results from alveolar damage—causing abnormal extracellular matrix (ECM) remodeling and impaired lung function. Early detection in mild, often asymptomatic stages is key to timely intervention. Although computed tomography (CT) scans are the most accurate detection method, pathological changes may occur before emphysema becomes visible, highlighting the need for non-invasive early detection approaches.
This study aimedto develop a proof-of-concept machine learning (ML) pipeline to identify patients with mild-stage emphysema using circulating biomarkers.
ML demonstrates potential for early-stage emphysema diagnosis through biomarker-driven methods. Quantifying fragments of ECM remodeling—driven by immune cell activity and collagen formation—could potentially serve as early diagnostic biomarkers in patients without lung function decline.
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Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic and fatal lung disease with limited treatment options. Fibroblast activation and ECM deposition is pivotal in development of IPF, thus inhibiting fibrogenesis and ECM deposition is crucial for anti-fibrotic approaches to treat IPF.
This study aims to prove that tankyrase inhibition reduces fibrogenesis induced by a fibrotic cocktail (FC) in primary human lung fibroblasts derived from IPF patients and decreases extracellular matrix biomarkers nordicPRO-C3 TM and nordicPRO-C6TM.
These findings highlight the potential of tankyrase inhibiton as a therapeutic target for IPF and support the use of the Scar–in-a-Jar model as an effective tool for IPF drug screening.
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Engineering liver fibrosis in a three-dimensional, extracellular matrixhydrogel disease model
Introduction
Modeling fibrosis requires replicating the mechano-chemical cues of the extracellular matrix (ECM), including binding sites, three-dimensionality, and biomechanics. To engineer a liver fibrosis model based on native, decellularized ECM with spatial and compositional integrity, layered on a hydrogel of poly(ethylene glycol) diacrylate (PEGDA) that provides tunable mechanical properties.
This model aims to support cell recolonization and facilitate the investigation of cell-matrix interactions, fibrogenic remodeling, and therapeutic screening in a physiologically relevant context.
HSCs colonize porcine liver ECM and synthesize new collagen. Biochemical signaling and biomechanical properties drive ECM deposition, recapitulating key features of the fibrotic niche. Upon treatment with relaxin-2, HSCs display an ECM-degrading activity. The ECM-hydrogel constructs exhibit no cytotoxicity, and polymer concentration can be tuned to modulate the mechanical properties of the ECM. Due to its anatomical similarity to human tissue, porcine ECM offers a biologically relevant scaffold for in vitro fibrosis modeling without the ethical concerns associated with live animal use.
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Bile acids drive fibroblast activation, fibrogenesis, interstitial matrix fibrosis and outcomes in PSC
Introduction
Fibrosis often originates from a persistent insult that damages epithelial and endothelial cells and activates chronic proinflammatory processes that impair the regular course of tissue repair[1].
A hallmark of fibrosis is the activation of fibroblasts leading to excessive production of type I, III, and VI collagens in the interstitial space of the extracellular matrix (ECM). Several drivers, including transforming growth factor-beta (TGF-β), have been identified as key drivers of fibroblast activation. While bile acids (BA) have been shown to correlate with the fibroblast activation marker PRO-C3 in biliary diseases, their precise role in the process of fibrogenesis remains unclear.
The present work aims to investigate the relationship between bile acids and markers of ECM formation and degradation during anti-fibrotic therapy (an engineered FGF-19; NCT02704364 analogue;) and related prognostic ability of biomarkers reflecting fibroblast activity in PSC.
Fibroblast activation and collagen formation play a crucial role in determining outcomes in PSC. The data suggests that bile acids activate fibroblast driving fibrogenesis, and that lowering of bile acids attenuate the fibrotic drive. Lowering fibroblast activity may have positive effects on liver related outcomes in PSC.
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Weight dependent, weight independent and non-pharmacological effects on fibroblast activity in metabolic dysfunction associated steatotic liver disease (MASLD)
Introduction
It is well established that fibroblasts are activated by metabolic dysfunction and are a central component of liver function decline and death. Fibroblast activities, both type III and type VI collagen formation, have been shown to be highly prognostic for outcome of liver, heart and kidney related events in MAFLD populations. Fibroblast activity in man, may both be inhibited by weight dependent and independent mechanisms, and as such monitoring fibroblast activities is essential.
Pharmacological and non-pharmacological induction of weight loss results in different deactivation of fibroblasts activities, which may have divergent efficacy on heart and liver related outcomes. Furthermore, weight dependent and independent mechanisms of deactivation fibroblasts may result in additional effects on bone and muscle. This understanding may be needed when designing the optimal intervention strategy, including possible combination regimens, for the individual MAFLD patient.
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A composite score of nordicPRO-C6™ and platelet count is prognostic for liver-related outcomes in patients with chronic hepatitis C
Introduction
There is a need to identify prognostic markers for patients with chronic liver disease at increased risk of developing a liver-related outcome. Endotrophin, a signal peptide that is a driver of fibroblast activation and promotion of fibroinflammatory disease, can be assessed using the nordicPRO-C6™assay. Our aim was to explore the diagnostic utility of a composite score of nordicPRO-C6™/Platelets to predict liver-related outcomes in The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (HALT-C).
A composite score combining PRO-C6 and platelet count has been shown to improve the prognosis of liver-related outcomes in patients with chronic hepatitis C (CHC) cirrhosis compared to PRO-C6 or platelet count alone. Notably, among CHC patients with cirrhosis, those classified in the low-score group experienced no liver-related outcomes for more than two years. This PRO-C6/platelet count composite score may therefore offer a more effective tool for risk stratification in CHC patients with advanced liver disease. However, further validation is needed to confirm its prognostic value in CHC patients following sustained virologic response (SVR), as well as in individuals with other forms of advanced-stage chronic liver disease.
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The crosslinked type III collagen biomarker, CTX-III, reflects fibrosis resolution and is related to intervention and survival in chronic liver disease
Introduction
Liver fibrosis progresses by deposing increasing amounts of crosslinked collagens in the extracellular matrix (ECM), destroying the liver parenchyma in the process. Treatments that hamper fibrosis could trigger the degradation of crosslinked fragments. A biomarker that measures the destruction of crosslinked collagen could open a window into the evolution of disease and the effectivity of therapy. We hypothesize that circulating fragments of crosslinked collagen type III (CTX-III) can be detected and measured to reflect fibrinolysis, and thus biomark fibrosis resolution.
CTX-III is a biomarker engineered to detect enzymatically degraded crosslinked collagen type III. Its levels have been shown to increase after bariatric surgery, suggesting it is possible to measure systemic response to surgical intervention. Additionally, the CTX-III:PRO-C3 ratio detects a subpopulation of cirrhotic patients who respond to TIPS with significantly longer survival.
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Degradation of the alveolar basement membrane type IV collagen alpha-3 chain is associated with antifibrotic treatment and pulmonary hypertension in idiopathic pulmonary fibrosis
Introduction
Idiopathic pulmonary fibrosis (IPF) is a rare but devastating disease with inevitable progression and high mortality. Currently, Pirfenidone and Nintedanib are the only approved antifibrotic treatment options to slow disease progression. Additionally, a pulmonary hypertension (PH) complication can further worsen disease outcome and quality of life. Forced vital capacity (FVC) is currently the most employed endpoint in clinical trials to monitor disease progression for antifibrotic treatment (Tx) development.
Molecularly, the extracellular matrix is subjected to excessive, pathological remodeling during IPF progression. Type IV collagen (COL4) is a critical part of the basement membrane that support the epithelium and crucial to cellular integrity. Mature COL4 are trimers that can be derived from six different alpha-chains, wherein the a3-chain is predominantly expressed in alveoli. Other trimers are expressed ubiquitously.
The aim was to investigate potential associations with antifibrotic Tx and PH in IPF patients by comparing serological levels of alveolar basement membrane degradation by a fragment of the COL4 alpha-3 chain (C4Ma3) with a fragment of more general remodelling by the alpha-1 chain (PRO-C4).
The COL4 alpha-3 chain has limited tissue distribution and is crucial for alveolar function. In this study, higher levels of COL4 alpha-3 chain degradation (C4Ma3) was:
found in IPF with PH.
associated with no antifibrotic treatment, indicating a pharmacodynamic potential.
In comparison, the COL4 alpha-1 chain marker PRO-C4, indicating ubiquitous basement membrane remodeling, did not show statistically different levels between any of the groups compared in this study. This could highlight the fact that damage done within alveoli are especially relevant when assessing the effect of antifibrotic Tx and PH in IPF.
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