Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization

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Barreto , G , Senturk , B , Colombo , L , Brück , O , Neidenbach , P , Salzmann , G , Zenobi-Wong , M & Rottmar , M 2020 , ' Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization ' , Osteoarthritis and Cartilage , vol. 28 , no. 1 , pp. 92-101 . https://doi.org/10.1016/j.joca.2019.10.011 , https://doi.org/10.1016/j.joca.2019.10.011

Title: Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization
Author: Barreto, Goncalo; Senturk, B.; Colombo, L.; Brück, O.; Neidenbach, P.; Salzmann, G.; Zenobi-Wong, M.; Rottmar, M.
Contributor: University of Helsinki, Department of Health Sciences and Technology (D-HEST)
University of Helsinki, Department of Clinical Chemistry and Hematology
Date: 2020-01
Language: eng
Number of pages: 10
Belongs to series: Osteoarthritis and Cartilage
ISSN: 1063-4584
URI: http://hdl.handle.net/10138/309886
Abstract: Objective: Lumican (LUM) is a major extracellular matrix glycoprotein in adult articular cartilage and its expression is known to be upregulated upon cartilage degeneration. LUM is associated with the pathogen-associated molecular pattern (PAMP) activation of the TLR4 signalling cascade, with TLR4 being highly associated with inflammation in rheumatic diseases. However, the main role of the LUM structural molecule in osteoarthritis (OA) remains elusive. The aim of this study was, therefore, to understand the role of LUM during TLR4-mediated activation in OA. Methods: After measuring LUM levels in synovial fluid (SF) of OA patients and lipopolysaccharide (LPS)-induced TLR4 activation, the role of LUM in the expression of pro-inflammatory molecules and cartilage degradation was assessed in vitro and ex vivo in a cartilage explant model. Primary macrophage activation and polarization were studied upon LUM co-stimulation with LPS. Results: We demonstrate that LUM is not only significantly upregulated in SF from OA patients compared to healthy controls, but also that LUM increases lipopolysaccharide (LPS)-induced TLR4 activation. Furthermore, we show that a pathophysiological level of LUM augments the LPS-induced TLR4 activation and expression of downstream pro-inflammatory molecules, resulting in extensive cartilage degradation. LUM co-stimulation with LPS also provided a pro-inflammatory stimulus, upregulating primary macrophage activation and polarization towards the M1-like phenotype. Conclusions: These findings strongly support the role of LUM as a mediator of PAMP-induced TLR4 activation of inflammation, cartilage degradation, and macrophage polarization in the OA joint and potentially other rheumatic diseases. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Subject: Lumican
Osteoarthritis
Cartilage matrix
Inflammation
Macrophages
Toll-like receptor 4
LEUCINE-RICH PROTEOGLYCANS
BIOMARKERS
CHONDROCYTE
FIBROBLASTS
RECEPTORS
IMMUNITY
DISEASE
BURDEN
INJURY
3111 Biomedicine
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