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Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • N. Sharma
  • P. Drobinski
  • A. Kayed
  • Z. Chen
  • C. F. Kjelgaard-Petersen
  • T. Gantzel
  • M. A. Karsdal
  • M. Michaelis
  • C. Ladel
  • A. C. Bay-Jensen
  • S. Lindemann
  • C. S. Thudium
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftOsteoarthritis and Cartilage
Vol/bind28
Udgave nummer5
Sider (fra-til)658-668
Antal sider11
ISSN1063-4584
DOI
StatusUdgivet - maj 2020

Bibliografisk 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:
© 2019 Osteoarthritis Research Society International

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

ID: 66399626