Osteogenesis imperfecta (OI), a heritable disorder caused by abnormalities in synthesis or processing of type I collagen, is characterized by skeletal fragility. Type I collagen interacts with multiple components of the extracellular matrix (ECM) including other collagens types. Thus, alterations in...
January 4, 2021
Journal:
Bone
Author:
Nicol L, Srikanth P, Henriksen K, Sun S, Smith R, Karsdal MA, Nagamani SCS, Shapiro J, Lee B, Leder BZ, Orwoll E
Osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, all have one clear common denominator; an altered turnover of bone. However, this may be more complex than a simple change in bone matrix and mineral turnover. While these diseases share a common tissue axis, thei...
December 21, 2020
Journal:
BMC Musculoskelet Disord.
Author:
Thudium CS, Nielsen SH, Sardar S, Mobasheri A, van Spil WE, Lories R, Henriksen K, Bay-Jensen AC, Karsdal MA.
Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a cri...
December 20, 2020
Journal:
Nat Metab
Author:
Leslie J, Macia MG, Luli S, Worrell JC, Reilly WJ, Paish HL, Knox A, Barksby BS, Gee LM, Zaki MYW, Collins AL, Burgoyne RA, Cameron R, Bragg C, Xu X, Chung GW, Brown CDA, Blanchard AD, Nanthakumar CB, Karsdal M, Robinson SM, Manas DM, Sen G, French J, White SA, Murphy S, Trost M, Zakrzewski JL, Klein U, Schwabe RF, Mederacke I, Nixon C, Bird T, Teuwen LA, Schoonjans L, Carmeliet P, Mann J, Fisher AJ, Sheerin NS, Borthwick LA, Mann DA, Oakley F.
Introduction: Metabolic-associated fatty liver disease is common, with fibrosis the major determinant of adverse outcomes. Population-based screening tools with high diagnostic accuracy for the staging of fibrosis are lacking. Methods: Three independent cohorts, 2 with both liver biopsy and liver s...
November 26, 2020
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Eslam M, Wong GL, Hashem AM, Chan HL, Nielsen MJ, Leeming DJ, Chan AW, Chen Y, Duffin KL, Karsdal M, Schattenberg JM, George J, Wong VW
Background and aims: A vulnerable plaque is an atherosclerotic plaque that is rupture-prone with a higher risk to cause cardiovascular symptoms such as myocardial infarction or stroke. Mimecan or osteoglycin is a small leucine-rich proteoglycan, important for collagen fibrillogenesis, that has been ...
November 25, 2020
Journal:
atherosclerosis
Author:
Tengryd C, Nielsen SH, Cavalera M, Bengtsson E, Genovese F, Karsdal M, Dunér P, Orho-Melander M, Nilsson J, Edsfeldt A, Gonçalves I
New therapeutic strategies are needed for the growing unmet clinical needs in liver disease and fibrosis. Platelet activation and PDGF activity are recognized as important therapeutic targets; however, no therapeutic approach has yet addressed these two upstream drivers of liver fibrosis. We therefo...
November 20, 2020
Journal:
Biomaterials
Author:
Kabra H, Walimbe T, Stuart K, Indey C, Jalgaonkar S, Ikwa E, Skurnac T, Chen J, Woolley A, Snead NM, Bachtell N, Leeming DJ, Karsdal M, Prestwich G, Panitch A, Paderi J
Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We eva...
November 20, 2020
Journal:
J Hepatocell Carcinoma
Author:
Jensen C, Holm Nielsen S, Eslam M, Genovese F, Nielsen MJ, Vongsuvanh R, Uchila R, van der Poorten D, George J, Karsdal MA, Leeming DJ, Willumsen N.
Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We eva...
November 20, 2020
Journal:
J Hepatocell Carcinoma
Author:
Jensen C, Holm Nielsen S, Eslam M, Genovese F, Nielsen MJ, Vongsuvanh R, Uchila R, van der Poorten D, George J, Karsdal MA, Leeming DJ, Willumsen N.
Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a cri...
November 20, 2020
Journal:
Nat Metab
Author:
Leslie J, Macia MG, Luli S, Worrell JC, Reilly WJ, Paish HL, Knox A, Barksby BS, Gee LM, Zaki MYW, Collins AL, Burgoyne RA, Cameron R, Bragg C, Xu X, Chung GW, Brown CDA, Blanchard AD, Nanthakumar CB, Karsdal M, Robinson SM, Manas DM, Sen G, French J, White SA, Murphy S, Trost M, Zakrzewski JL, Klein U, Schwabe RF, Mederacke I, Nixon C, Bird T, Teuwen LA, Schoonjans L, Carmeliet P, Mann J, Fisher AJ, Sheerin NS, Borthwick LA, Mann DA, Oakley
Background: Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with...
Introduction: Variants in collagen-related genes COL1A1, COL3A1, COL5A1 and COL5A2 are associated with Ehlers-Danlos syndrome (EDS), a heterogeneous group of connective tissue disorders strongly associated with increased bleeding. Of patients with incompletely explained bleeding diathesis, a relativ...
November 20, 2020
Journal:
Haemophilia
Author:
Fager Ferrari M, Zetterberg E, Rossing M, Manon-Jensen T, Pehrsson M, Karsdal MA, Lykkesfeldt J, Leinoe E
Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal epithelial repair resulting in a hypercoagulable state with intra-alveolar accumulation of fibrin and alveolar basement membrane destruction. This study aimed to investigate if the combination of two serological bi...
November 19, 2020
Journal:
Lancet Respir Med
Author:
Sand JMB, Rønnow SR, Langholm LL, Karsdal MA, Manon-Jensen T, Tal-Singer R, Miller BE, Vestbo J, Leeming DJ
Connective tissue (ConT) remodeling is an essential process in tissue regeneration, where a balanced replacement of old tissue by new tissue occurs. This balance is disturbed in chronic diseases, often autoimmune diseases, usually resulting in the buld up of fibrosis and a gradual loss of organ func...
November 12, 2020
Journal:
Review, Autoimmunity
Author:
Karsdal MA, Kraus VB, Shevell D, Bay-Jensen AC, Schattenberg J, Rambabu Surabattula R, Schuppan D
The effect of direct-acting antiviral (DAA) therapy on extracellular matrix (ECM) turnover, a prominent feature of chronic hepatitis C (CHC), is unknown. ECM protein degradation and formation generate fragments reflecting the tissue turnover balance when quantified in the blood. PRO-C3 and PRO-C4 re...
October 15, 2020
Journal:
J Viral Hepat
Author:
Laursen TL, Villesen IF, Leeming DJ, Karsdal MA, Sølund C, Tarp B, Kristensen LH, Holmboe CH, Leuthcher P, Laursen AL, Gudmann NS, Grønbaek H
Different stimulants might induce different extracellular matrix profiles. It is essential to gain an understanding and quantification of these changes to allow for focused anti-fibrotic drug development. This study investigated the expression of extracellular matrix by dermal fibroblast mimicking f...
October 14, 2020
Journal:
Sci Rep
Author:
Juhl P, Bondesen S, Hawkins CL, Karsdal MA, Bay-Jensen AC, Davies MJ, Siebuhr AS
Background: Tissue released blood-based biomarkers can provide insight into drug mode of action and response. To understand the changes in extracellular matrix turnover, we analyzed biomarkers associated with joint tissue turnover from a phase 3, randomized, placebo-controlled study of baricitinib i...
October 12, 2020
Journal:
Arthritis Res Ther
Author:
Thudium CS, Bay-Jensen AC, Cahya S, Dow ER, Karsdal MA, Koch AE, Zhang W, Benschop RJ
Background: Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) receptor induce a response in only a subgroup of patients with metastatic melanoma. Previous research suggests that transforming growth factor beta signaling and a collagen-rich peritumoral stroma (tumor ...
October 8, 2020
Journal:
J Immunother Cancer
Author:
Hurkmans DP, Jensen C, Koolen SLW, Aerts J, Karsdal MA, Mathijssen RHJ, Willumsen N
he PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The...
October 7, 2020
Journal:
J Clin Med
Author:
Yepes-Calderón M, Sotomayor CG, Rasmussen DGK, Hijmans RS, Te Velde-Keyzer CA, van Londen M, van Dijk M, Diepstra A, Berger SP, Karsdal MA, Bemelman FJ, de Fijter JW, Kers J, Florquin S, Genovese F, Bakker SJL, Sanders JS, Van Den Born J
Abstract Introduction: Hepatic fibrosis is the excessive synthesis and deposition of extracellular matrix including collagen in the tissue. Chronic liver insult leads to progressive parenchymal damage, portal hypertension, and cirrhosis. Determination of hepatic collagen by invasive liver biopsy ...
September 24, 2020
Journal:
Expert Rev Mol Diagn
Osteoarthritis (OA) is associated with cartilage breakdown, brought about by ADAMTS-5 mediated aggrecan degradation followed by MMP-derived aggrecan and type II collagen degradation. We investigated a novel anti-ADAMTS-5 inhibiting Nanobody® (M6495) on cartilage turnover ex vivo. Bovine cartilage (B...
Objective: Dysregulation of type I collagen metabolism has a great impact on human health. We have previously seen that matrix metalloproteinase-degraded type I collagen (C1M) is associated with early death and age-related pathologies. To dissect the biological impact of type I collagen dysregulatio...
September 20, 2020
Journal:
Neurol Genet
Author:
Tang ME, Blair JPM, Bager CL, Bay-Jensen AC, Henriksen K, Christiansen C, Karsdal MA.
A T-cell permissive tumor microenvironment, characterized by the presence of activated T cells and low fibrotic activity is crucial for response to immune checkpoint inhibitors (ICIs). Granzyme B has been shown to promote T-cell migration through the basement membrane by the degradation of type IV c...
September 20, 2020
Journal:
Cancers (Basel)
Author:
Jensen C, Sinkeviciute D, Madsen DH, Önnerfjord P, Hansen M, Schmidt H, Karsdal MA, Svane IM, Willumsen N
Introduction: Anti-tumor necrosis factor (TNF) therapy is effective in inducing remission in Crohn's disease in 60% of patients. No serological biomarkers are available, which can predict response to anti-TNF. We aimed to investigate serological markers of collagen turnover reflecting tissue inflamm...
September 11, 2020
Journal:
Clin Transl Gastroenterol
Author:
van Haaften WT, Mortensen JH, Dige AK, Grønbæk H, Hvas CL, Bay-Jensen AC, Karsdal MA, Olinga P, Manon-Jensen T, Dijkstra G
Introduction: Anti-tumor necrosis factor (TNF) therapy is effective in inducing remission in Crohn's disease in 60% of patients. No serological biomarkers are available, which can predict response to anti-TNF. We aimed to investigate serological markers of collagen turnover reflecting tissue inflamm...
September 11, 2020
Journal:
Clin Transl Gastroenterol
Author:
van Haaften WT, Mortensen JH, Dige AK, Grønbæk H, Hvas CL, Bay-Jensen AC, Karsdal MA, Olinga P, Manon-Jensen T, Dijkstra G
Introduction: Anti-tumor necrosis factor (TNF) therapy is effective in inducing remission in Crohn's disease in 60% of patients. No serological biomarkers are available, which can predict response to anti-TNF. We aimed to investigate serological markers of collagen turnover reflecting tissue inflamm...
September 11, 2020
Journal:
Clin Transl Gastroenterol
Author:
van Haaften WT, Mortensen JH, Dige AK, Grønbæk H, Hvas CL, Bay-Jensen AC, Karsdal MA, Olinga P, Manon-Jensen T, Dijkstra G
Background & aims: Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated...
September 3, 2020
Journal:
JHEP Rep
Author:
Vesterhus M, Nielsen MJ, Hov JR, Saffioti F, Manon-Jensen T, Leeming DJ, Moum B, Boberg KM, Pinzani M, Karlsen TH, Karsdal MA, Thorburn D
Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA pa...
August 18, 2020
Journal:
Sci Rep
Author:
J P M Blair A-C Bay-Jensen M H Tang P Frederiksen C Bager M Karsdal S Brunak
Fibrosis is often heterogeneously distributed, and classical biopsies do not reflect this. Noninvasive methods for renal fibrosis have been developed to follow chronic kidney diseases (CKD) and to monitor anti-fibrotic therapy. In this study, we combined two approaches to assess fibrosis regression ...
Background: Lung epithelial damage, activation of the wound healing cascade, and remodeling of the extracellular matrix (ECM) play a major role in chronic obstructive pulmonary disease (COPD). The pro-peptide of type VI collagen has been identified as the hormone endotrophin. Endotrophin has been sh...
Evidence indicate that the brain-specific protein, brevican, is proteolytically cleaved during neurodegeneration, hence positioning fragments of brevican as potential blood biomarkers of neurodegenerative diseases, such as dementia. We aimed to develop two assays capable of detecting the brevican N-...
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