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Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors

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Harvard

Sharma, N, Drobinski, P, Kayed, A, Chen, Z, Kjelgaard-Petersen, CF, Gantzel, T, Karsdal, MA, Michaelis, M, Ladel, C, Bay-Jensen, AC, Lindemann, S & Thudium, CS 2020, 'Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors', Osteoarthritis and Cartilage, bind 28, nr. 5, s. 658-668. https://doi.org/10.1016/j.joca.2019.11.002

APA

Sharma, N., Drobinski, P., Kayed, A., Chen, Z., Kjelgaard-Petersen, C. F., Gantzel, T., Karsdal, M. A., Michaelis, M., Ladel, C., Bay-Jensen, A. C., Lindemann, S., & Thudium, C. S. (2020). Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors. Osteoarthritis and Cartilage, 28(5), 658-668. https://doi.org/10.1016/j.joca.2019.11.002

CBE

Sharma N, Drobinski P, Kayed A, Chen Z, Kjelgaard-Petersen CF, Gantzel T, Karsdal MA, Michaelis M, Ladel C, Bay-Jensen AC, Lindemann S, Thudium CS. 2020. Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors. Osteoarthritis and Cartilage. 28(5):658-668. https://doi.org/10.1016/j.joca.2019.11.002

MLA

Vancouver

Author

Sharma, N. ; Drobinski, P. ; Kayed, A. ; Chen, Z. ; Kjelgaard-Petersen, C. F. ; Gantzel, T. ; Karsdal, M. A. ; Michaelis, M. ; Ladel, C. ; Bay-Jensen, A. C. ; Lindemann, S. ; Thudium, C. S. / Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors. I: Osteoarthritis and Cartilage. 2020 ; Bind 28, Nr. 5. s. 658-668.

Bibtex

@article{9ec52d8778214f558e7800acf839e2de,
title = "Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors",
abstract = "Objective: Links between pain and joint degradation are poorly understood. We investigated the role of activation of Toll-like receptors (TLR) by cartilage metabolites in initiating and maintaining the inflammatory loop in OA causing joint destruction. Methods: Synovial membrane explants (SMEs) were prepared from OA patients{\textquoteright} synovial biopsies. SMEs were cultured for 10 days under following conditions: culture medium alone, OSM + TNFα, TLR2 agonist - Pam2CSK4, Pam3CSK4 or synthetic aggrecan 32-mer, TLR4 agonist - Lipid A. Release of pro-inflammatory and degradation biomarkers (acMMP3 and C3M) were measured by ELISA in conditioned media along with IL-6. Additionally, human cartilage was digested with ADAMTS-5, with or without the ADAMTS-5 inhibiting nanobody - M6495. Digested cartilage solution (DCS) and synthetic 32-mer were tested for TLR activation in SEAP based TLR reporter assay. Results: Western blotting confirmed TLR2 and TLR4 in untreated OA synovial biopsies. TLR agonists showed an increase in release of biomarkers - acMMP3 and C3M in SME. Synthetic 32-mer showed no activation in the TLR reporter assay. ADAMTS-5 degraded cartilage fragments activated TLR2 in vitro. Adding M6495 – an anti-ADAMTS-5 inhibiting nanobody{\textregistered}, blocked ADAMTS-5-mediated DCS TLR2 activation. Conclusion: TLR2 is expressed in synovium of OA patients and their activation by synthetic ligands causes increased tissue turnover. ADAMTS-5-mediated cartilage degradation leads to release of aggrecan fragments which activates the TLR2 receptor in vitro. M6495 suppressed cartilage degradation by ADAMTS-5, limiting the activation of TLR2. In conclusion, pain and joint destruction may be linked to generation of ADAMTS-5 cartilage metabolites.",
keywords = "Inflammation, Innate immunity, Osteoarthritis (OA), Synovial membrane, Toll like receptors (TLRs)",
author = "N. Sharma and P. Drobinski and A. Kayed and Z. Chen and Kjelgaard-Petersen, {C. F.} and T. Gantzel and Karsdal, {M. A.} and M. Michaelis and C. Ladel and Bay-Jensen, {A. C.} and S. Lindemann and Thudium, {C. S.}",
note = "Funding Information: This work was supported by the Danish research foundation (DRF) and Nordic bioscience. The DRF was not involved in the study design, collection, analysis and interpretation of data, writing or deciding to submit the manuscript for publication. Nordic bioscience was involved in the study design, collection, analysis, interpretation of data, writing the manuscript and the decision to submit the manuscript for publication.We would like to acknowledge the Danish Research Foundation for supporting and funding this work. We would also like to thank all the patients who donated their cartilage. Funding Information: This work was supported by the Danish research foundation (DRF) and Nordic bioscience. The DRF was not involved in the study design, collection, analysis and interpretation of data, writing or deciding to submit the manuscript for publication. Nordic bioscience was involved in the study design, collection, analysis, interpretation of data, writing the manuscript and the decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2019 Osteoarthritis Research Society International Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = may,
doi = "10.1016/j.joca.2019.11.002",
language = "English",
volume = "28",
pages = "658--668",
journal = "Osteoarthritis and Cartilage",
issn = "1063-4584",
publisher = "W.B./Saunders Co. Ltd",
number = "5",

}

RIS

TY - JOUR

T1 - Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors

AU - Sharma, N.

AU - Drobinski, P.

AU - Kayed, A.

AU - Chen, Z.

AU - Kjelgaard-Petersen, C. F.

AU - Gantzel, T.

AU - Karsdal, M. A.

AU - Michaelis, M.

AU - Ladel, C.

AU - Bay-Jensen, A. C.

AU - Lindemann, S.

AU - Thudium, C. S.

N1 - Funding Information: This work was supported by the Danish research foundation (DRF) and Nordic bioscience. The DRF was not involved in the study design, collection, analysis and interpretation of data, writing or deciding to submit the manuscript for publication. Nordic bioscience was involved in the study design, collection, analysis, interpretation of data, writing the manuscript and the decision to submit the manuscript for publication.We would like to acknowledge the Danish Research Foundation for supporting and funding this work. We would also like to thank all the patients who donated their cartilage. Funding Information: This work was supported by the Danish research foundation (DRF) and Nordic bioscience. The DRF was not involved in the study design, collection, analysis and interpretation of data, writing or deciding to submit the manuscript for publication. Nordic bioscience was involved in the study design, collection, analysis, interpretation of data, writing the manuscript and the decision to submit the manuscript for publication. Publisher Copyright: © 2019 Osteoarthritis Research Society International Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/5

Y1 - 2020/5

N2 - Objective: Links between pain and joint degradation are poorly understood. We investigated the role of activation of Toll-like receptors (TLR) by cartilage metabolites in initiating and maintaining the inflammatory loop in OA causing joint destruction. Methods: Synovial membrane explants (SMEs) were prepared from OA patients’ synovial biopsies. SMEs were cultured for 10 days under following conditions: culture medium alone, OSM + TNFα, TLR2 agonist - Pam2CSK4, Pam3CSK4 or synthetic aggrecan 32-mer, TLR4 agonist - Lipid A. Release of pro-inflammatory and degradation biomarkers (acMMP3 and C3M) were measured by ELISA in conditioned media along with IL-6. Additionally, human cartilage was digested with ADAMTS-5, with or without the ADAMTS-5 inhibiting nanobody - M6495. Digested cartilage solution (DCS) and synthetic 32-mer were tested for TLR activation in SEAP based TLR reporter assay. Results: Western blotting confirmed TLR2 and TLR4 in untreated OA synovial biopsies. TLR agonists showed an increase in release of biomarkers - acMMP3 and C3M in SME. Synthetic 32-mer showed no activation in the TLR reporter assay. ADAMTS-5 degraded cartilage fragments activated TLR2 in vitro. Adding M6495 – an anti-ADAMTS-5 inhibiting nanobody®, blocked ADAMTS-5-mediated DCS TLR2 activation. Conclusion: TLR2 is expressed in synovium of OA patients and their activation by synthetic ligands causes increased tissue turnover. ADAMTS-5-mediated cartilage degradation leads to release of aggrecan fragments which activates the TLR2 receptor in vitro. M6495 suppressed cartilage degradation by ADAMTS-5, limiting the activation of TLR2. In conclusion, pain and joint destruction may be linked to generation of ADAMTS-5 cartilage metabolites.

AB - Objective: Links between pain and joint degradation are poorly understood. We investigated the role of activation of Toll-like receptors (TLR) by cartilage metabolites in initiating and maintaining the inflammatory loop in OA causing joint destruction. Methods: Synovial membrane explants (SMEs) were prepared from OA patients’ synovial biopsies. SMEs were cultured for 10 days under following conditions: culture medium alone, OSM + TNFα, TLR2 agonist - Pam2CSK4, Pam3CSK4 or synthetic aggrecan 32-mer, TLR4 agonist - Lipid A. Release of pro-inflammatory and degradation biomarkers (acMMP3 and C3M) were measured by ELISA in conditioned media along with IL-6. Additionally, human cartilage was digested with ADAMTS-5, with or without the ADAMTS-5 inhibiting nanobody - M6495. Digested cartilage solution (DCS) and synthetic 32-mer were tested for TLR activation in SEAP based TLR reporter assay. Results: Western blotting confirmed TLR2 and TLR4 in untreated OA synovial biopsies. TLR agonists showed an increase in release of biomarkers - acMMP3 and C3M in SME. Synthetic 32-mer showed no activation in the TLR reporter assay. ADAMTS-5 degraded cartilage fragments activated TLR2 in vitro. Adding M6495 – an anti-ADAMTS-5 inhibiting nanobody®, blocked ADAMTS-5-mediated DCS TLR2 activation. Conclusion: TLR2 is expressed in synovium of OA patients and their activation by synthetic ligands causes increased tissue turnover. ADAMTS-5-mediated cartilage degradation leads to release of aggrecan fragments which activates the TLR2 receptor in vitro. M6495 suppressed cartilage degradation by ADAMTS-5, limiting the activation of TLR2. In conclusion, pain and joint destruction may be linked to generation of ADAMTS-5 cartilage metabolites.

KW - Inflammation

KW - Innate immunity

KW - Osteoarthritis (OA)

KW - Synovial membrane

KW - Toll like receptors (TLRs)

UR - http://www.scopus.com/inward/record.url?scp=85077717562&partnerID=8YFLogxK

U2 - 10.1016/j.joca.2019.11.002

DO - 10.1016/j.joca.2019.11.002

M3 - Journal article

C2 - 31734268

AN - SCOPUS:85077717562

VL - 28

SP - 658

EP - 668

JO - Osteoarthritis and Cartilage

JF - Osteoarthritis and Cartilage

SN - 1063-4584

IS - 5

ER -

ID: 66399626