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Matrix metalloproteinase-13 expression in response to double-stranded RNA in human chondrocytes

Lookup NU author(s): Dr Marta Radwan, Christos Gavriilidis, Professor John Robinson, Emeritus Professor Drew Rowan, Professor David YoungORCiD

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Abstract

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.

Publication metadata

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

Year: 2013

Volume: 65

Issue: 5

Pages: 1290-1301

Print publication date: 17/01/2013

ISSN (print): 0004-3591

ISSN (electronic): 1529-0131

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/art.37868

DOI: 10.1002/art.37868

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