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  1. Article ; Online: A Highly Sensitive Biomarker of Type II Collagen C-Terminal Pro-Peptide Associated with Cartilage Formation.

    Port, Helena / Bay-Jensen, Anne-Christine / He, Yi / Karsdal, Morten A / Gantzel, Thorbjørn / Thudium, Christian S / Holm Nielsen, Signe

    International journal of molecular sciences

    2022  Volume 24, Issue 1

    Abstract: The type II collagen C-terminal pro-peptide is one of the most abundant polypeptides in cartilage. The purpose of this study was to develop a competitive chemiluminescence enzyme-linked immunosorbent assay, CALC2, targeting this pro-peptide as a marker ... ...

    Abstract The type II collagen C-terminal pro-peptide is one of the most abundant polypeptides in cartilage. The purpose of this study was to develop a competitive chemiluminescence enzyme-linked immunosorbent assay, CALC2, targeting this pro-peptide as a marker of cartilage formation. Technical assay parameters were evaluated. CALC2 level was measured after in vitro cleavage of recombinant type II collagen with bone morphogenetic protein-1 (BMP-1) and treatment of ex vivo human osteoarthritis (OA) cartilage explant model (HEX) with insulin-like growth factor-1 (IGF-1). Serum CALC2 levels were assessed in 18 patients with rheumatoid arthritis (RA), 19 patients with ankylosing spondylitis (AS), and 18 age- and sex-matched controls in cohort 1 and 8 patients with OA and 14 age- and sex-matched controls in cohort 2. Type II collagen cleavage with BMP-1 increased the CALC2 level. IGF-1 treatment increased the CALC2 levels in HEX compared with the untreated explants (p < 0.05). Results were confirmed using Western blot analysis. CALC2 levels were decreased in the patients with RA and AS compared with the healthy controls (p = 0.01 and p = 0.02, respectively). These findings indicate that CALC2 may be a novel biomarker of type II collagen formation. However, further preclinical and clinical studies are required to validate these findings.
    MeSH term(s) Humans ; Collagen Type II ; Insulin-Like Growth Factor I/therapeutic use ; Cartilage ; Arthritis, Rheumatoid ; Peptides/therapeutic use ; Osteoarthritis ; Spondylitis, Ankylosing/drug therapy ; Biomarkers ; Cartilage, Articular
    Chemical Substances Collagen Type II ; Insulin-Like Growth Factor I (67763-96-6) ; Peptides ; Biomarkers
    Language English
    Publishing date 2022-12-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24010454
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The activation fragment of PAR2 is elevated in serum from patients with rheumatoid arthritis and reduced in response to anti-IL6R treatment.

    Kalogera, Stefania / He, Yi / Bay-Jensen, Anne-Christine / Gantzel, Thorbjørn / Sun, Shu / Manon-Jensen, Tina / Karsdal, Morten Asser / Thudium, Christian S

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 24285

    Abstract: Osteoarthritis (OA) and rheumatoid arthritis (RA) are serious and painful diseases. Protease-activated receptor 2 (PAR2) is involved in the pathology of both OA and RA including roles in synovial hyperplasia, cartilage destruction, osteophyogenesis and ... ...

    Abstract Osteoarthritis (OA) and rheumatoid arthritis (RA) are serious and painful diseases. Protease-activated receptor 2 (PAR2) is involved in the pathology of both OA and RA including roles in synovial hyperplasia, cartilage destruction, osteophyogenesis and pain. PAR2 is activated via cleavage of its N-terminus by serine proteases. In this study a competitive ELISA assay was developed targeting the 36-amino acid peptide that is cleaved and released after PAR2 activation (PRO-PAR2). Technical assay parameters including antibody specificity, intra- and inter-assay variation (CV%), linearity, accuracy, analyte stability and interference were evaluated. PRO-PAR2 release was confirmed after in vitro cleavage of PAR2 recombinant protein and treatment of human synovial explants with matriptase. Serum levels of 22 healthy individuals, 23 OA patients and 15 RA patients as well as a subset of RA patients treated with tocilizumab were evaluated. The PRO-PAR2 antibody was specific for the neo-epitope and intra-inter assay CV% were 6.4% and 5.8% respectively. In vitro cleavage and matriptase treated explants showed increased PRO-PAR2 levels compared to controls. In serum, PRO-PAR2 levels were increased in RA patients and decreased in RA patients treated with tocilizumab. In conclusion, PRO-PAR2 may be a potential biomarker for monitoring RA disease and pharmacodynamics of treatment.
    MeSH term(s) Adult ; Aged ; Antibodies/chemistry ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal, Humanized/therapeutic use ; Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/immunology ; Arthritis, Rheumatoid/therapy ; Biomarkers/metabolism ; Cartilage/metabolism ; Epitopes/chemistry ; Female ; Humans ; Immunoassay ; Linear Models ; Male ; Middle Aged ; Osteoarthritis/metabolism ; Receptor, PAR-2/blood ; Receptors, Interleukin-6/antagonists & inhibitors ; Reproducibility of Results ; Serine Endopeptidases ; Synovial Fluid/metabolism ; Synovial Membrane/metabolism ; Young Adult
    Chemical Substances Antibodies ; Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Biomarkers ; Epitopes ; F2RL1 protein, human ; IL6R protein, human ; Receptor, PAR-2 ; Receptors, Interleukin-6 ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase (EC 3.4.21.-) ; tocilizumab (I031V2H011)
    Language English
    Publishing date 2021-12-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-03346-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis.

    Kjelgaard-Petersen, Cecilie F / Platt, Adam / Braddock, Martin / Jenkins, Martin A / Musa, Kishwar / Graham, Emma / Gantzel, Thorbjørn / Slynn, Gillian / Weinblatt, Michael E / Karsdal, Morten A / Thudium, Christian S / Bay-Jensen, Anne-C

    Arthritis & rheumatology (Hoboken, N.J.)

    2018  Volume 70, Issue 9, Page(s) 1419–1428

    Abstract: Objective: Rheumatoid arthritis (RA) is a chronic and degenerative autoimmune joint disease that leads to disability, reduced quality of life, and increased mortality. Although several synthetic and biologic disease-modifying antirheumatic drugs are ... ...

    Abstract Objective: Rheumatoid arthritis (RA) is a chronic and degenerative autoimmune joint disease that leads to disability, reduced quality of life, and increased mortality. Although several synthetic and biologic disease-modifying antirheumatic drugs are available, there is still a medical need for novel drugs that control disease progression. As only 10% of experimental drug candidates for treatment of RA that enter phase I trials are eventually registered by the Food and Drug Administration, there is an immediate need for translational tools to facilitate early decision-making in drug development. In this study, we aimed to determine if the inability of fostamatinib (a small molecule inhibitor of Syk) to demonstrate sufficient efficacy in phase III of a previous clinical study could have been predicted earlier in the development process.
    Methods: Biomarkers of bone, cartilage, and interstitial matrix turnover (C-telopeptide of type I collagen [CTX-I], matrix metalloproteinase-derived types I, II, and III collagen neoepitopes [C1M, C2M, and C3M]) were measured in 450 serum samples from the Oral Syk Inhibition in Rheumatoid Arthritis 1 study (OSKIRA-1, a phase III clinical study of the efficacy of fostamatinib in RA) at baseline and follow-up. Additionally, the same biomarkers were subsequently measured in conditioned media from osteoclast, cartilage, and synovial membrane cultured with the active metabolite of fostamatinib, R406, to assess the level of suppression induced by the drug.
    Results: In OSKIRA-1 serum samples and osteoclast and cartilage cultures, fostamatinib suppressed the levels of CTX-I and C2M. In OSKIRA-1 serum samples and synovial membrane cultures, fostamatinib did not mediate any clinical or preclinical effect on either C1M or C3M, which have previously been associated with disease response and efficacy.
    Conclusion: These data demonstrate that translational biomarkers are a potential tool for early assessment and decision-making in drug development for RA treatment.
    MeSH term(s) Antirheumatic Agents/pharmacology ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/metabolism ; Biomarkers/analysis ; Cartilage/drug effects ; Cartilage/metabolism ; Collagen/drug effects ; Collagen/metabolism ; Drug Development/methods ; Drug Discovery/methods ; Humans ; Oxazines/pharmacology ; Pyridines/pharmacology ; Synovial Membrane/drug effects ; Synovial Membrane/metabolism ; Translational Medical Research/methods
    Chemical Substances Antirheumatic Agents ; Biomarkers ; Oxazines ; Pyridines ; Collagen (9007-34-5) ; fostamatinib (SQ8A3S5101)
    Language English
    Publishing date 2018-07-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2756371-6
    ISSN 2326-5205 ; 2326-5191
    ISSN (online) 2326-5205
    ISSN 2326-5191
    DOI 10.1002/art.40527
    Database MEDical Literature Analysis and Retrieval System OnLINE

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