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Lookup NU author(s): Dr Marta Radwan,
Professor John Robinson,
Emeritus Professor Drew Rowan,
Professor David YoungORCiD
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Objectives: To investigate the mechanism of matrix metalloproteinase (MMP)-13 expression in chondrocytes via pattern recognition receptors (PRRs) for double-stranded (ds) RNA. Methods: Differential expression of PRRs was determined by real-time RT-PCR of RNA from osteoarthritis (OA) and neck of femur (NOF) fracture patients. Isolated human articular chondrocytes and the chondrosarcoma cell-line SW1353 were activated with different molecular sized poly(I:C) as a dsRNA mimic, and gene expression and protein changes monitored by real-time RT-PCR and immunoblotting, respectively. Results: dsRNA-signalling moieties ‘Toll-like receptor 3’ (TLR3), ‘retinoid-inducible gene 1’ (RIG-I) and ‘nucleotide-binding oligomerization domain, leucine rich repeat containing X1’ (NLRX1) were all differentially expressed in our OA versus NOF expression screen. Depletion of the dsRNA-sensing receptors TLR3, RIG-I or ‘Melanoma differentiation-associated gene-5’ (MDA5) suppressed the induction of MMP13 by poly(I:C), regardless of its delivery. Additionally, depletion of the downstream transcription factor interferon regulatory factor 3 (IRF3) resulted in reduced induction of MMP13 by poly(I:C). Conclusions: dsRNA-signalling in chondrocytes requires a range of PRRs including TLR3, RIG-I and MDA5 for the full-induction of MMP13, thus providing tight regulation of a gene critical for maintenance of cartilage integrity. Our data add to the understanding of MMP13 regulation, which is essential before such mechanisms can be exploited to alleviate the cartilage destruction associated with OA.
Author(s): Radwan M, Gavriilidis C, Robinson JH, Davidson R, Clark IM, Rowan AD, Young DA
Publication type: Article
Publication status: Published
Journal: Arthritis & Rheumatism
Print publication date: 17/01/2013
ISSN (print): 0004-3591
ISSN (electronic): 1529-0131
Publisher: John Wiley & Sons, Inc.
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