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Book ; Online ; E-Book: Biochemistry of Collagens, Laminins and Elastin

Karsdal, Morten A.

Structure, Function and Biomarkers

2024

Author's details	Morten Karsdal
MeSH term(s)	Collagen/chemistry ; Elastin/chemistry ; Laminin/chemistry ; Extracellular Matrix Proteins/chemistry
Keywords	Biochemical markers ; Biochemistry ; Extracellular matrix proteins
Subject code	572/.67
Language	English
Size	1 online resource (0 pages)
Edition	Third edition.
Publisher	Mica H. Haley
Publishing place	Oxford, England
Document type	Book ; Online ; E-Book
Remark	Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
ISBN	0-443-15618-2 ; 9780443156175 ; 978-0-443-15618-2 ; 0443156174
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long-acting dual amylin and calcitonin receptor agonist improves insulin-mediated glycaemic control and controls body weight.

Melander, Simone Anna / Larsen, Anna Thorsø / Karsdal, Morten Asser / Henriksen, Kim

British journal of pharmacology

2024

Abstract: Background and purpose: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring ... ...

Abstract	Background and purpose: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D. Experimental approach: Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg Key results: Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation. Conclusion and implications: The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits.
Language	English
Publishing date	2024-02-20
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.16329
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Article ; Online: Treatment sequencing using the dual amylin and calcitonin receptor agonist KBP-336 and semaglutide results in durable weight loss.

Thorsø Larsen, Anna / Karsdal, Morten A / Henriksen, Kim

European journal of pharmacology

2023 Volume 954, Page(s) 175837

Abstract: Objective: Long-acting dual amylin and calcitonin receptor agonists (DACRAs) hold great promise as potential treatments for obesity and its associated comorbidities. These agents have demonstrated beneficial effects on body weight, glucose control, and ... ...

Abstract	Objective: Long-acting dual amylin and calcitonin receptor agonists (DACRAs) hold great promise as potential treatments for obesity and its associated comorbidities. These agents have demonstrated beneficial effects on body weight, glucose control, and insulin action mirroring the effects observed with glucagon-like peptide-1 (GLP-1) agonist treatment. Strategies aimed at enhancing and prolonging treatment efficacy include treatment sequencing and combination therapy. Here, we sought to investigate the impact of switching between or combining treatment with the DACRA KBP-336 and the GLP-1 analog semaglutide in fed rats with obesity induced by a high-fat diet (HFD). Methods: Two studies were performed in which HFD-induced obese Sprague Dawley rats were switched between treatment with KBP-336 (4.5 nmol/kg, Q3D) and semaglutide (50 nmol/kg, Q3D) or a combination of the two. Treatment efficacy on weight loss and food intake was evaluated, and glucose tolerance was assessed by oral glucose tolerance tests. Results: KBP-336 and semaglutide monotherapy resulted in a similar reduction in body weight and food intake. Treatment sequencing resulted in continuous weight loss and all monotherapies resulted in similar weight loss independent of the treatment regimen (P < 0.001 compared to vehicle). The combination of KBP-336 and semaglutide significantly improved the weight loss compared to either monotherapy alone (P < 0.001), which was evident in the adiposity at the study end. All treatments improved glucose tolerance, with the KBP-effect on insulin sensitivity as the dominant response. Conclusions: These findings highlight KBP-336 as a promising anti-obesity therapy both alone, in treatment sequencing, and in combination with semaglutide or other incretin-based therapies.
MeSH term(s)	Rats ; Animals ; Amylin Receptor Agonists/pharmacology ; Receptors, Calcitonin/agonists ; Islet Amyloid Polypeptide ; Rats, Sprague-Dawley ; Weight Loss ; Body Weight ; Obesity/drug therapy ; Glucagon-Like Peptide 1 ; Bone Density Conservation Agents ; Glucose ; Glucagon-Like Peptide-1 Receptor ; Hypoglycemic Agents ; Diabetes Mellitus, Type 2
Chemical Substances	Amylin Receptor Agonists ; Receptors, Calcitonin ; semaglutide (53AXN4NNHX) ; Islet Amyloid Polypeptide ; Glucagon-Like Peptide 1 (89750-14-1) ; Bone Density Conservation Agents ; Glucose (IY9XDZ35W2) ; Glucagon-Like Peptide-1 Receptor ; Hypoglycemic Agents
Language	English
Publishing date	2023-06-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2023.175837
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Article ; Online: Changes in type VI collagen degradation reflect clinical response to treatment in rheumatoid arthritis patients treated with tocilizumab.

Thudium, Christian S / Frederiksen, Peder / Karsdal, Morten A / Bay-Jensen, Anne-Christine

Arthritis research & therapy

2024 Volume 26, Issue 1, Page(s) 3

Abstract: Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation in multiple articular joints, causing pain, joint damage, and loss of joint function. Despite the successful development of disease-modifying therapies, ... ...

Abstract	Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation in multiple articular joints, causing pain, joint damage, and loss of joint function. Despite the successful development of disease-modifying therapies, the heterogeneity of RA means that a significant proportion of patients respond poorly to treatment. This highlights the need for personalized medicine and predictive biomarkers to optimize treatment efficacy, safety, and cost. This study aimed to explore the relationship between type VI collagen (Col VI) remodeling and clinical response to anti-IL-6 receptor treatment. Methods: Type VI collagen degradation was quantified using the C6M biomarker, a fragment of type VI collagen degraded by MMPs. Longitudinal differences in average biomarker levels between placebo and treatment groups were estimated using linear mixed models. The predictive capacity of the marker based on change from baseline to 4 weeks was analyzed using logistic regression. Results: Both 4 mg and 8 mg doses of Tocilizumab (TCZ) reduced serum C6M concentrations compared to the placebo. Furthermore, C6M levels were more reduced in patients responding to treatment compared to early non-responders. A lower early reduction in C6M was associated with reduced odds of ACR treatment response and lowered disease activity. Conclusion: These findings suggest that quantifying type VI collagen turnover may aid in identifying patients less likely to respond to treatment, indicating a new path towards optimizing patient care. Further studies are needed to validate these findings and explore the underlying mechanisms driving the observed relationships.
MeSH term(s)	Humans ; Collagen Type VI ; Arthritis, Rheumatoid/drug therapy ; Antibodies, Monoclonal, Humanized/therapeutic use ; Treatment Outcome ; Biomarkers ; Antirheumatic Agents/therapeutic use
Chemical Substances	tocilizumab (I031V2H011) ; Collagen Type VI ; Antibodies, Monoclonal, Humanized ; Biomarkers ; Antirheumatic Agents
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-023-03242-0
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Article ; Online: Neutrophil activity in serum as a biomarker for multiple sclerosis.

Holm Nielsen, Signe / Karsdal, Morten / Bay-Jensen, Anne-Christine

Multiple sclerosis and related disorders

2023 Volume 79, Page(s) 105005

Abstract: Multiple Sclerosis (MS) is an immune-mediated inflammatory disease affecting the central nervous system (CNS). Current treatments target neuroinflammation, but only limit the disease progression by reducing brain atrophy and a worsening in ... ...

Abstract	Multiple Sclerosis (MS) is an immune-mediated inflammatory disease affecting the central nervous system (CNS). Current treatments target neuroinflammation, but only limit the disease progression by reducing brain atrophy and a worsening in neurodegenerative damage. A blood-based biomarker of neutrophil activity, CPa9-HNE, holds the potential as a diagnostic biomarker in MS. We evaluated the CPa9-HNE biomarker in healthy donors, and patients with primary progressive MS (PPMS) and relapsing/remitting MS (RRMS). The CPa9-HNE was able to discriminate between the healthy donors and PPMS and RPMS with an AUROC>0.97. The CPa9-HNE biomarker may be used to assess patients' eligibility for targeted treatments.
MeSH term(s)	Humans ; Multiple Sclerosis/diagnosis ; Multiple Sclerosis, Chronic Progressive/diagnosis ; Neutrophils ; Multiple Sclerosis, Relapsing-Remitting/diagnosis ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-09-09
Publishing country	Netherlands
Document type	Letter
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2023.105005
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Article ; Online: Supramolecularly stabilized diabetes drugs.

Henriksen, Kim / Karsdal, Morten A

Nature biomedical engineering

2020 Volume 4, Issue 5, Page(s) 481–482

MeSH term(s)	Animals ; Diabetes Mellitus ; Glucagon ; Insulin ; Islet Amyloid Polypeptide ; Swine
Chemical Substances	Insulin ; Islet Amyloid Polypeptide ; Glucagon (9007-92-5) ; pramlintide (D3FM8FA78T)
Language	English
Publishing date	2020-05-11
Publishing country	England
Document type	Journal Article ; Comment
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-020-0558-1
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Article ; Online: Osteoarthritis: Current Molecular Biomarkers and the Way Forward.

Kraus, Virginia Byers / Karsdal, Morten A

Calcified tissue international

2020 Volume 109, Issue 3, Page(s) 329–338

Abstract: 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 ... ...

Abstract	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 homeostasis and/or joint survival-measures such as provided by imaging biomarkers, molecular biomarkers and joint replacement frequency, respectively. Although biomarkers supporting investigational drug use and drug approval include surrogate endpoints that may not necessarily reflect or directly correlate with the clinical outcome of interest, a formal biomarker qualification process currently exists that is a rigorous three stage process that yields biomarker approvals (or denials) for specific contexts of use. From a cost perspective, biochemical biomarkers are the 'ones to beat'; however, even well-validated biomarkers may not cross the translation gaps for eventual use in healthcare unless they offer an advantage in terms of cost per quality adjusted life year. This review summarizes the case FOR and AGAINST biomarkers in drug development and highlights the current data for a subset of biomarkers in the osteoarthritis research field informing on cartilage homeostasis, joint inflammation and altered subchondral bone remodeling.
MeSH term(s)	Biomarkers ; Bone Remodeling ; Cartilage, Articular ; Humans ; Osteoarthritis/diagnosis ; Osteoarthritis, Knee
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-05-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	304266-2
ISSN	1432-0827 ; 0944-0747 ; 0008-0594 ; 0171-967X
ISSN (online)	1432-0827
ISSN	0944-0747 ; 0008-0594 ; 0171-967X
DOI	10.1007/s00223-020-00701-7
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Article: Lot-to-Lot Variance in Immunoassays-Causes, Consequences, and Solutions.

Luo, Yunyun / Pehrsson, Martin / Langholm, Lasse / Karsdal, Morten / Bay-Jensen, Anne-Christine / Sun, Shu

Diagnostics (Basel, Switzerland)

2023 Volume 13, Issue 11

Abstract: Immunoassays, which have gained popularity in clinical practice and modern biomedical research, play an increasingly important role in quantifying various analytes in biological samples. Despite their high sensitivity and specificity, as well as their ... ...

Abstract	Immunoassays, which have gained popularity in clinical practice and modern biomedical research, play an increasingly important role in quantifying various analytes in biological samples. Despite their high sensitivity and specificity, as well as their ability to analyze multiple samples in a single run, immunoassays are plagued by the problem of lot-to-lot variance (LTLV). LTLV negatively affects assay accuracy, precision, and specificity, leading to considerable uncertainty in reported results. Therefore, maintaining consistency in technical performance over time presents a challenge in reproducing immunoassays. In this article, we share our two-decade-long experience and delve into the reasons for and locations of LTLV, as well as explore methods to mitigate its effects. Our investigation identifies potential contributing factors, including quality fluctuation in critical raw materials and deviations in manufacturing processes. These findings offer valuable insights to developers and researchers working with immunoassays, emphasizing the importance of considering lot-to-lot variance in assay development and application.
Language	English
Publishing date	2023-05-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics13111835
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Article ; Online: Regulation of tumor immunity and immunotherapy by the tumor collagen extracellular matrix.

Flies, Dallas B / Langermann, Solomon / Jensen, Christina / Karsdal, Morten A / Willumsen, Nicholas

Frontiers in immunology

2023 Volume 14, Page(s) 1199513

Abstract: It has been known for decades that the tumor extracellular matrix (ECM) is dysfunctional leading to loss of tissue architecture and promotion of tumor growth. The altered ECM and tumor fibrogenesis leads to tissue stiffness that act as a physical barrier ...

Abstract	It has been known for decades that the tumor extracellular matrix (ECM) is dysfunctional leading to loss of tissue architecture and promotion of tumor growth. The altered ECM and tumor fibrogenesis leads to tissue stiffness that act as a physical barrier to immune cell infiltration into the tumor microenvironment (TME). It is becoming increasingly clear that the ECM plays important roles in tumor immune responses. A growing body of data now indicates that ECM components also play a more active role in immune regulation when dysregulated ECM components act as ligands to interact with receptors on immune cells to inhibit immune cell subpopulations in the TME. In addition, immunotherapies such as checkpoint inhibitors that are approved to treat cancer are often hindered by ECM changes. In this review we highlight the ways by which ECM alterations affect and regulate immunity in cancer. More specifically, how collagens and major ECM components, suppress immunity in the complex TME. Finally, we will review how our increased understanding of immune and immunotherapy regulation by the ECM is leading towards novel disruptive strategies to overcome immune suppression.
MeSH term(s)	Humans ; Collagen ; Extracellular Matrix ; Immunotherapy ; Immunosuppression Therapy ; Neoplasms/therapy ; Tumor Microenvironment
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2023-08-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1199513
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Article: The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy.

Sonne, Nina / Larsen, Anna Thorsø / Karsdal, Morten Asser / Henriksen, Kim

Biomedicines

2022 Volume 10, Issue 10

Abstract: Background: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA ( ... ...

Abstract	Background: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles. Methods: To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague-Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats. Results: KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control. Conclusion: different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar.
Language	English
Publishing date	2022-09-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10102365
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