MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis--validation of two novel biomarker assays
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 re…
Journal:
Authors:
- Sand JM,
- Larsen L,
- Hogaboam C,
- Martinez F,
- Han M,
- Røssel Larsen M,
- Nawrocki A,
- Zheng Q,
- Karsdal MA,
- Leeming DJ,
Type VI collagen turnover-related peptides-novel serological biomarkers of muscle mass and anabolic response to loading in young men
BACKROUND:
Immobilization-induced loss of muscle mass is a complex phenomenon with several parallels to sarcopenic and cachectic muscle loss. Muscle is a large organ with a protein turnover that is orders of magnitude larger than most other tissues. Thus, we hypothesize that muscle loss and regain …
Journal:
Authors:
- Nedergaard A,
- Sun S,
- Karsdal MA,
- Henriksen K,
- Kjær M,
- Lou Y,
- He Y,
- Zheng Q,,
- Suetta C,
Osteoclasts are not crucial for hematopoietic stem cell maintenance in adult mice
The osteoclast is vital for establishment of normal hematopoiesis in the developing animal. However, its role for maintenance of hematopoiesis in adulthood is more controversial. To shed more light on this process, we transplanted hematopoietic stem cells from two osteopetrotic mouse models, with la…
Journal:
Authors:
- Flores C,
- Moscatelli I,
- Thudium CS,
- Gudmann NS,
- Thomsen JS,
- Brüel A,
- Karsdal MA,
- Henriksen K,
- Richter J,
Value of biomarkers in osteoarthritis: current status and perspectives
Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of t…
Journal:
Authors:
- Lotz M,
- Martel-Pelletier J,
- Christiansen C,
- Brandi ML,
- Bruyère O,
- Chapurlat R,
- Collette J,
- Cooper C,
- Giacovelli G,
- Kanis JA,
- Karsdal MA,
- Kraus V,
- Lems WF,
- Meulenbelt I,
- Pelletier JP,
- Raynauld JP,
- Reiter-Niesert S,
- Rizzoli R,
- Sandell LJ,
- Van Spil WE,
- Reginster JY,
Extracellular matrix specific protein fingerprints measured in serum can separate pancreatic cancer patients from healthy controls
BACKGROUND:
Pancreatic cancer (PC) is an aggressive disease with an urgent need for biomarkers. Hallmarks of PC include increased collagen deposition (desmoplasia) and increased matrix metalloproteinase (MMP) activity. The aim of this study was to investigate whether protein fingerprints of specifi…
Journal:
Authors:
- Willumsen N,
- Bager CL,
- Leeming DJ,
- Smith V,
- Karsdal MA,
- Dornan D,
- Bay-Jensen AC,
Lentiviral gene transfer of TCIRG1 into peripheral blood CD34(+) cells restores osteoclast function in infantile malignant osteopetrosis
Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by non-functional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to restore the resorpt…
Journal:
Authors:
- Moscatelli I,
- Thudium CS,
- Flores C,
- Schulz A,
- Askmyr M,
- Gudmann NS,
- Andersen NM,
- Porras O,
- Karsdal MA,
- Villa A,
- Fasth A,
- Henriksen K,
- Richter J,
Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension
BACKGROUND:
The hepatic venous pressure gradient (HVPG) is an invasive, but important diagnostic and prognostic marker in cirrhosis with portal hypertension (PHT). During cirrhosis, remodelling of fibrotic tissue by matrix metalloproteinases (MMPs) is a permanent process generating small fragments …
Journal:
Authors:
- Leeming D,
- Karsdal MA,
- Bendtsen F,
- Trebicka J,
- Nielsen MJ,
- Christiansen C,
- Møller S,
- Krag A,
Metabolic health in families enriched for longevity is associated with low prevalence of hand osteoarthritis and influences OA biomarker profiles
OBJECTIVES:
Individual metabolic characteristics and age-related changes may affect osteoarthritis (OA) risk as well as levels of potential OA biomarkers such as serum cartilage oligomeric protein (sCOMP) and urinary cross-linked C-telopeptide of type 2 collagen (uCTX2). We investigated hand OA and…
Journal:
Authors:
- Bos SD,
- Beekman M,
- Maier AB,,
- Karsdal MA,
- Kwok WY,
- Bay-Jensen AC,
- Kloppenburg M,
- Slagboom PE,
- Meulenbelt I,
Musculoskeletal ageing and primary prevention
Loss of musculoskeletal mass and function is a natural ageing trait, reinforced by an unhealthy life style. Loss of bone (osteoporosis) and muscle (sarcopaenia) are conditions whose prevalence are increasing because of the change in population distribution in the western world towards an older mean …
Journal:
Authors:
- Nedergaard A,
- Henriksen K,
- Karsdal MA,
- Christiansen C,
The development and characterization of an ELISA specifically detecting the active form of cathepsin K
OBJECTIVE:
Cathepsin K plays essential roles in bone resorption and is intensely investigated as a therapeutic target for the treatment of osteoporosis. Hence an assessment of the active form of cathepsin K may provide important biological information in metabolic bone diseases, such as osteoporosi…
Journal:
Authors:
- Sun S,
- Karsdal MA,
- Bay-Jensen AC,
- Sørensen MG,
- Zheng Q,
- Dziegiel MH,
- Maksymowych WP,
- Henriksen K,
Association of systemic collagen type IV formation with survival among patients undergoing hemodialysis
OBJECTIVE:
The 7S domain of collagen type IV (P4NP_7S) assessed in plasma represents systemic collagen type IV formation. The objective of the study was to investigate the association of systemic collagen type IV formation with survival among patients undergoing hemodialysis.
METHODS:
We perfor…
Journal:
Authors:
- Leeming DJ,
- Karsdal MA,
- Rasmussen LM,
- Scholze A,
- Tepel M,
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…
Journal:
Authors:
Serological identification of fast progressors of structural damage with rheumatoid arthritis
INTRODUCTION:
Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruct…
Journal:
Authors:
- Siebuhr AS,
- Bay-Jensen AC,
- Leeming DJ,
- Plat A,
- Byrjalsen I,
- Christiansen C,
- van de Heijde D,
- Karsdal MA,
Circulating protein fragments of cartilage and connective tissue degradation are diagnostic and prognostic markers of rheumatoid arthritis and ankylosing spondylitis
Inflammation driven connective tissue turnover is key in rheumatic diseases, such as ankylosing spondylitis (AS). Few biomarkers are available for measuring disease prognosis or the efficacy of interventions applied in these tissue-related conditions. Type II collagen is the primary structural prote…
Journal:
Authors:
- Bay-Jensen AC,
- Wichuk S,
- Byrjalsen I,
- Leeming DJ,
- Morency N,
- Christiansen C,
- Karsdal MA,
- Maksymowych WP,
Serum markers of the extracellular matrix remodeling reflect antifibrotic therapy in bile-duct ligated rats
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 refle…
Journal:
Authors:
- Schierwagen R,
- Leeming DJ,
- Klein S,
- Granzow M,
- Nielsen MJ,
- Sauerbruch T,
- Krag A,
- Karsdal MA,
- Trebicka J,
Lentiviral gene transfer of TCIRG1 into peripheral blood CD34+ cells restores osteoclast function in infantile malignant osteopetrosis
Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by non-functional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to restore the resorpt…
Journal:
Authors:
- Moscatelli I,
- Thudium CS,
- Flores C,
- Schulz A,
- Askmyr M,
- Gudmann KN,
- Andersen NM,
- Porras O,
- Karsdal MA,
- Villa A,
- Fasth A,
- Henriksen K,
- Richter J,
Autosomal dominant osteopetrosis revisited: lessons from recent studies
Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the …
Journal:
Authors:
- Bollerslev J,
- Henriksen K,
- Nielsen MF,
- Brixen K,
- Van Hul W,
Acute Myocardial Infarction and Pulmonary Diseases Result in Two Different Degradation Profiles of Elastin as Quantified by Two Novel ELISAs
BACKGROUND:
Elastin is a signature protein of the arteries and lungs, thus it was hypothesized that elastin is subject to enzymatic degradation during cardiovascular and pulmonary diseases. The aim was to investigate if different fragments of the same protein entail different information associated…
Journal:
Authors:
- Skjøt-Arkil H,
- Clausen RE,
- Rasmussen LM,
- Wang W,
- Wang Y,
- Zheng Q,
- Mickley H,
- Saaby L,
- Diederichsen AC,
- Lambrechtsen J,
- Martinez FJ,
- Hogaboam CM,
- Han M,
- Larsen MR,
- Nawrocki A,
- Vainer B,
- Krustrup D,
- Bjørling-Poulsen M,
- Karsdal MA,
- Leeming DJ,
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 …
Journal:
Authors:
- Barascuk N,
- Genovese F,
- Larsen L,
- Byrjalsen I,
- Zheng Q,
- Sun S,
- Hosbond S,
- Poulsen TS,
- Diederichsen A,
- Jensen JM,
- Mickley H,
- Register TC,
- Rasmussen LM,
- Leeming DJ,
- Christiansen C,
- Karsdal MA,
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…
Journal:
Authors:
Menopause, estrogens and frailty
The controversy surrounding the results from the Women's Health Initiative (WHI) trials published a decade ago caused a significant decline in the use of menopausal hormone replacement therapy. However, these results have been vehemently contested and several lines of evidence suggest that in perime…
Journal:
Authors:
- Nedergaard A,
- Henriksen K,
- Karsdal MA,
- Christiansen C,
Peptidyl arginine deiminase inhibitor effect on hepatic fibrogenesis in a CCl4 pre-clinical model o2,454f liver fibrosis
Having previously shown that levels of the citrullinated vimentin peptide VICM are raised in liver fibrosis in rats, we aimed to investigate whether inhibition of citrullination as measured by VICM levels could affect fibrogenesis. Methods: Fibrogenesis was evaluated by quantitative histology and ci…
Journal:
Authors:
- Vassiliadis E,
- Veidal SS,
- Kristiansen MN,
- Hansen C,
- Jorgensen M,
- Leeming DJ,
- Karsdal MA,
An enzyme-generated fragment of tau measured in serum shows an inverse correlation to cognitive function
OBJECTIVE:
Alzheimer's disease (AD) is a devastating neurological disease characterized by pathological proteolytic cleavage of tau protein, which appears to initiate death of the neurons. The objective of this study was to investigate whether a proteolytic fragment of the tau protein could serve a…
Journal:
Authors:
- Henriksen K,
- Wang Y,
- Sørensen MG,
- Barascuk N,
- Suhy J,
- Pedersen JT,
- Duffin KL,
- Dean RA,
- Pajak M,
- Christiansen C,
- Zheng Q,
- Karsdal MA,
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…
Journal:
Authors:
- Genovese F,
- Barascuk N,
- Larsen L,
- Nawrocki A,
- Li Y,
- Zheng Q,
- Wang J,
- Veidal SS,
- Leeming DJ,
- Karsdal MA,
Peptidyl arginine deiminase inhibitor effect on hepatic fibrogenesis in a CCl4 pre-clinical model of liver fibrosis
Having previously shown that levels of the citrullinated vimentin peptide VICM are raised in liver fibrosis in rats, we aimed to investigate whether inhibition of citrullination as measured by VICM levels could affect fibrogenesis.
METHODS:
Fibrogenesis was evaluated by quantitative histology an…
Journal:
Authors:
- Vassiliadis E,
- Veidal SS,
- Kristiansen MN,
- Hansen C,
- Jorgensen M,
- Leeming DJ,
- Karsdal M,
Role of hormones in cartilage and joint metabolism: understanding an unhealthy metabolic phenotype in osteoarthritis
OBJECTIVE:
Joint health is affected by local and systemic hormones. It is well accepted that systemic factors regulate the metabolism of joint tissues, and that substantial cross-talk between tissues actively contributes to homeostasis. In the current review, we try to define a subtype of osteoarth…
Journal:
Authors:
- Bay-Jensen AC,
- Slagboom E,
- Chen-An P,
- Alexandersen P,
- Qvist P,
- Christiansen C,
- Meulenbelt I,
- Karsdal MA,
The development and characterization of a competitive ELISA for measuring active ADAMTS-4 in a bovine cartilage ex vivo model
ADAMTS-4 (aggrecanase1) is believed to play an important role in the degradation of aggrecan during the progression of joint diseases. ADAMTS-4 is synthesized as a latent pro-enzyme that requires the removal of the pro-domain, exposing the N-terminal neoepitope, to achieve activity. We developed a m…
Journal:
Authors:
- He Y,
- Zheng Q,
- Simonsen O,
- Petersen KK,
- Christiansen TG,
- Karsdal MA,
- Bay-Jensen AC,
The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters
AIM:
The present study describes the assessment of true formation of type III collagen in different pathologies using a neo-epitope specific competitive Enzyme-linked immunosorbent assay (ELISA) towards the N-terminal propeptide of type III collagen (PRO-C3).
METHODS:
The monoclonal antibody wa…
Journal:
Authors:
- Nielsen MJ,
- Nedergaard AF,
- Sun S,
- Veidal SS,
- Larsen L,
- Zheng Q,
- Suetta C,
- Henriksen K,
- Christiansen C,
- Karsdal MA,
- Leeming DJ,
Circulating citrullinated vimentin fragments reflect disease burden in ankylosing spondylitis and have prognostic capacity for radiographic progression
OBJECTIVE:
Ankylosing spondylitis (AS) has been considered a seronegative rheumatic disease based on absent or low levels of antibodies against citrullinated proteins. The present study was undertaken to evaluate whether a citrullinated and matrix metalloproteinase-degraded fragment of vimentin (VI…
Journal:
Authors:
- Bay-Jensen AC,
- Karsdal MA,
- Vassiliadis E,
- Marcher-Mikkelsen K,
- Lories R,
- Christiansen C,
- Maksymowych WP,
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…
Journal:
Authors:
- Karsdal MA,
- Nielsen MJ,
- Sand JM,
- Henriksen K,
- Genovese F,
- Bay-Jensen AC,
- Adamkewicz JI,
- Christiansen C,
- Leeming DJ,
Serological muscle loss biomarkers: an overview of current concepts and future possibilities
BACKGROUND:
The skeletal muscle mass is the largest organ in the healthy body, comprising 30-40 % of the body weight of an adult man. It confers protection from trauma, locomotion, ventilation, and it represents a "sink" in glucose metabolism and a reservoir of amino acids to other tissues such as …
Journal:
Authors:
- Nedergaard A,
- Karsdal MA,
- Sun S,
- Henriksen K,
Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis
CONTEXT:
Treatment of osteoporosis with subcutaneous (SC) injections of rhPTH(1-34) or rhPTH(1-84) is associated with significant improvements in BMD and reductions in osteoporotic fractures. However, subcutaneous injections can be associated with discomfort and thus deteriorating compliance.
OB…
Journal:
Authors:
- Henriksen K,
- Andersen JR,
- Riis BJ,
- Mehta N,
- Tavakkol R,
- Alexandersen P,
- Byrjalsen I,
- Valter I,
- Nedergaard BS,
- Teglbjaerg CS,
- Stern W,
- Sturmer A,
- Mitta S,
- Nino AJ,
- Fitzpatrick LA,
- Christiansen C,
- Karsdal MA,
Protein fingerprinting of the extracellular matrix remodelling in a rat model of liver fibrosis--a serological evaluation
BACKGROUND/AIM:
We investigated nine novel biomarkers of extracellular matrix (ECM) remodelling in a rat model of liver fibrosis.
METHODS:
Liver fibrosis was induced in 52 male Wistar rats by inhalation of carbon tetrachloride and the level of hepatic fibrosis was assessed by Sirius red stainin…
Journal:
Authors:
- Leeming DJ,
- Byrjalsen I,
- Jiménez W,
- Christiansen C,
- Karsdal MA,
Investigation of chondrocyte hypertrophy and cartilage calcification in a full-depth articular cartilage explants model
Articular cartilage deterioration, which includes cartilage degradation and chondrocyte hypertrophy, is a hallmark of degenerative joint diseases (DJD). Chondrocyte hypertrophy is initiated in the deep layer of the cartilage; thus, a robust explants model for investigation of hypertrophy should incl…
Journal:
Authors:
- Chen-An P,
- Andreassen KV,
- Henriksen K,
- Karsdal MA,
- Bay-Jensen AC,
Oral salmon calcitonin protects against impaired fasting glycemia, glucose intolerance, and obesity induced by high-fat diet and ovariectomy in rats
OBJECTIVE:
Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects …
Journal:
Authors:
- Feigh M,
- Andreassen KV,
- Hjuler ST,
- Nielsen RH,
- Christiansen C,
- Henriksen K,
- Karsdal MA,
Atherofibrosis - a unique and common process of the disease pathogenesis of atherosclerosis and fibrosis - lessons for biomarker development
The hallmark of a variety of fibrotic diseases such as liver fibrosis, lung fibrosis, skin fibrosis and atherosclerosis is extensive extracellular matrix remodeling (ECMr) of the disease affected tissue. Inflammation often leads to tissue disruption and destruction, upon which locally released batte…
Journal:
Authors:
- Vassiliadis E,
- Barascuk N,
- Karsdal MA,
Bringing cancer serological diagnosis to a new level: focusing on HER2, protein ectodomain shedding and neoepitope technology
Cancer is a heterogeneous disease and consequently an exact diagnosis is as important as the actual therapy. Therefore, identification of novel diagnostic biomarker targets is urgently needed. Physiological and pathological changes are reflected by post-translational modifications of proteins. Each …
Journal:
Authors:
- Wang J,
- Willumsen N,
- Zheng Q,
- Xue Y,
- Karsdal M,
- Bay-Jensen AC,