A5017241198- Cell Adhesion Molecules Research
- Protease and Inhibitor Mechanisms
- Peptidase Inhibition and Analysis
- Platelet Disorders and Treatments
- Neonatal Respiratory Health Research
- Complement system in diseases
- Bone health and treatments
- Immune cells in cancer
- Wound Healing and Treatments
- Blood properties and coagulation
- CAR-T cell therapy research
- Cellular Mechanics and Interactions
- Nanoparticle-Based Drug Delivery
- S100 Proteins and Annexins
- Radiopharmaceutical Chemistry and Applications
- ATP Synthase and ATPases Research
- Bone Metabolism and Diseases
- Enzyme Structure and Function
- TGF-β signaling in diseases
- Signaling Pathways in Disease
- Dietary Effects on Health
- Biomarkers in Disease Mechanisms
- Angiogenesis and VEGF in Cancer
- Blood Coagulation and Thrombosis Mechanisms
- Bone and Dental Protein Studies
Rigshospitalet
2015-2025
University of Copenhagen
2012-2024
National Institute of Dental and Craniofacial Research
2013-2019
National Institutes of Health
2013-2019
Business Innovation Centre
2011
Tissue remodeling processes critically depend on the timely removal and of preexisting collagen scaffolds. Nevertheless, many aspects related to turnover this abundant extracellular matrix component in vivo are still incompletely understood. We therefore took advantage recent advances optical imaging develop an assay visualize situ identify cell types molecules involved process. Collagen introduced into dermis mice underwent cellular endocytosis a partially metalloproteinase–dependent manner...
Physiologic turnover of interstitial collagen is mediated by a sequential pathway in which fragmented pericellular collagenases, endocytosed receptors, and routed to lysosomes for degradation cathepsins. Here, we use intravital microscopy investigate if malignant tumors, are characterized high rates extracellular matrix turnover, utilize similar pathway. Tumors epithelial, mesenchymal, or neural crest origin all display vigorous endocytic degradation. The cells engaged this process...
Collagens make up the most abundant component of interstitial extracellular matrices and basement membranes. Collagen remodeling is a crucial process in many normal physiological events several pathological conditions. Some collagen subtypes contain specific carbohydrate side chains, function which poorly known. The endocytic receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 plays an important role matrix through its ability to internalize for lysosomal...
The long pentraxin 3 (PTX3) has been shown to be important in maintaining internal tissue homeostasis and protecting against fungal Aspergillus fumigatus infection. However, the molecular mechanisms of how these functions are elicited poorly delineated. Ficolin-1 is a soluble pattern recognition molecule that interacts with PTX3. We hypothesized heterocomplexes between ficolin-1 PTX3 might mediate signals necessary for sequestration altered self-cells A. fumigatus. were able show via its...
Increased remodeling of the extracellular matrix in malignant tumors has been shown to correlate with tumor aggressiveness and a poor prognosis. This involves degradation original (ECM) deposition new tumor-supporting ECM. The main constituent ECM is collagen turnover mainly occurs sequential manner, where initial proteolytic cleavage insoluble fibers followed by cellular internalization large well-defined fragments for lysosomal degradation. However, despite extensive research field, lack...
Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression this stroma-dense tumor. We generated site-specific offering high-affinity, cross-species reactivity, efficient internalization anti-uPAR monoclonal...
Members of the well-conserved mannose receptor (MR) protein family have been functionally implicated in diverse biological and pathological processes. Importantly, a proposed common function is internalization collagen for intracellular degradation occurring during bone development, cancer invasion, fibrosis protection. This functional relationship suggested by endocytic capability candidate collagen-binding domain. Here we conducted comparative investigation each member's ability to...
Abstract Fibrosis of the liver and its end‐stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts hepatic stellate cells display a net deposition collagen. This collagen is factor leading to dysfunction, thus making it crucially important understand both synthesis turnover mechanisms in this condition. Here we show that endocytic receptor, uPARAP/Endo180, determinant governing balance between degradation. Cirrhotic human livers...
// Christoffer Fagernæs Nielsen 1 , Sander Maarten van Putten Ida Katrine Lund Maria Carlsén Melander Kirstine Sandal Nørregaard Henrik Jessen Jürgensen 1, 3 Kristian Reckzeh Kristine Rothaus Christensen 2 Signe Ziir Ingvarsen Gårdsvoll Kamilla Ellermann Jensen 4 Petra Hamerlik Lars Henning Engelholm and Niels Behrendt The Finsen Laboratory, Rigshospitalet, Biotech Research Innovation Center (BRIC), Faculty of Health Medical Sciences, University Copenhagen,...
In osteosarcoma, a primary mesenchymal bone cancer occurring predominantly in younger patients, invasive tumour growth leads to extensive destruction. This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen receptor, uPARAP/Endo180, expressed on various cell types involved matrix turnover during normal growth. Human osteosarcoma specimens showed strong expression this receptor cells, along with the...
A well-coordinated remodeling of uncalcified collagen matrices is a pre-requisite for bone development and homeostasis. Collagen turnover proceeds through different pathways, either involving extracellular reactions exclusively, or being dependent on endocytic processes. Extracellular degradation requires the action secreted membrane attached collagenolytic proteases, whereas alternative pathway intracellularly after receptor-mediated uptake delivery to lysosomes. In this study we have...
Macrophage plasticity, cellular origin, and phenotypic heterogeneity are perpetual challenges for studies addressing the biology of this pivotal immune cell in development, homeostasis, tissue remodeling/repair. Consequently, a myriad macrophage subtypes has been described these contexts. To facilitate identification functional vivo, here we used flow cytometry-based assay that allows detailed phenotyping macrophages engaged extracellular matrix (ECM) degradation. Of five identified...
Matriptase is a membrane serine protease essential for epithelial development, homeostasis, and regeneration, as well central orchestrator of pathogenic pericellular signaling in the context inflammatory proliferative diseases. an unusual that its zymogen displays measurable enzymatic activity. Here, we used gain loss function genetics to investigate possible biological functions matriptase. Unexpectedly, transgenic mice mis-expressing zymogen-locked version matriptase epidermis displayed...
Abstract The membrane-anchored matrix metalloprotease MT1-MMP is a potent collagenolytic enzyme with well-established role in extracellular turnover and cellular invasion into collagen-rich tissues. highly expressed various types of cancer has been demonstrated to be directly involved several stages tumor progression, including primary growth, angiogenesis, metastasis. Osteosarcoma the most common type bone cancer. This disease characterized by invasive leading extensive destruction,...
Collectins such as mannose-binding lectin (MBL) and surfactant protein D (SP-D) become temporarily deposited in extravascular compartments after tissue injury perform immune-stimulatory or inflammation-limiting functions. However, their turnover mechanisms, necessary to prevent excessive damage, are virtually unknown. In this study, we show that fibroblasts injured tissues undertake the clearance of collectins by using endocytic collagen receptor uPARAP. cellular assays, several types were...
C-type lectins that contain collagen-like domains are known as collectins. These proteins present both in the circulation and extravascular compartments central players of innate immune system, contributing to first-line defenses against viral, bacterial, fungal pathogens. The collectins mannose-binding lectin (MBL) surfactant protein D (SP-D) regulated by tissue fibroblasts at sites via an endocytic mechanism governed urokinase plasminogen activator receptor-associated (uPARAP or Endo180),...
The proteins of the mannose receptor (MR) family share a common domain organization and have broad range biological functions. Urokinase plasminogen activator receptor-associated protein (uPARAP) (or Endo180) is member this plays an important role in extracellular matrix remodelling through interaction with its ligands, including collagens urokinase (uPAR). We report crystal structures first four domains uPARAP (also named ligand-binding region, LBR) at pH 7.4 Ca2+-bound Ca2+-free forms....
Thrombospondin-1 (TSP-1) is a matricellular protein with multitude of functions in the pericellular and extracellular environment. We report novel pathway for regulation TSP-1, governed by endocytic collagen receptor, uPARAP (urokinase plasminogen activator receptor-associated protein; MRC2 gene product, also designated Endo180, CD280). First, using proteomic approach unbiased identification ligands endocytosis, we identify TSP-1 as candidate ligand specific uptake uPARAP. then show that can...
Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression MM. Thus, to evaluate its potential use diagnostics therapy, we quantified by immunohistochemical H-score formalin-fixed paraffin-embedded bioptic/surgical human tissue samples microarrays. detected...