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Rheumatology Advance Access published online on March 5, 2009
Rheumatology, doi:10.1093/rheumatology/kep040
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A novel paradigm for dendritic cells as effectors of cartilage destruction

Rachel L. Lakey1, Tanya G. Morgan1, Andrew D. Rowan1, John D. Isaacs1, Tim E. Cawston1 and Catharien M. U. Hilkens1

1Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

Correspondence to: Catharien M. U. Hilkens, Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. E-mail: catharien.hilkens{at}newcastle.ac.uk


  Abstract

Objective. Dendritic cells (DCs) are enriched in RA synovium and have been implicated in the pathogenesis of RA primarily through their ability to present autoantigen and activate T cells. However, whether DCs play an effector role in cartilage destruction is unknown. The aim of this study was to investigate whether DCs can induce collagen release from cartilage and the mechanism involved.

Methods. Human monocyte-derived DCs (mDCs) were activated with CD40 ligand (CD40L) to mimic DC–T-cell interaction, and supernatants were incubated with cartilage explants. Hydroxyproline was assessed as a measure of collagen release and collagenolytic activity was measured by a bioassay using tritiated collagen. TNF-{alpha} in DC supernatants was measured by specific ELISA.

Results. Supernatants from CD40L-activated mDCs, but not unstimulated mDCs, strongly induced the destruction of cartilage collagen. mDC supernatants did not contain collagenases but did induce collagenolytic activity in cartilage explants. Neutralization of TNF-{alpha} in mDC supernatants completely abolished collagenolysis.

Conclusions. This study shows that mDCs, upon CD40-ligation, induce cartilage collagen degradation through an indirect mechanism via the production of TNF-{alpha}. Our data suggest a potential important role for mDC-derived TNF-{alpha} in RA, which is in line with the previously reported observations that DCs are a major source of TNF-{alpha} in early autoimmune lesions and that anti-TNF-{alpha} therapeutics effectively suppress joint damage in RA patients. We propose that DCs can act as effectors in cartilage destruction, adding a new aspect to the functional role of DCs in RA pathogenesis.

KEY WORDS: Dendritic cells, Cartilage destruction, Collagen resorption, Tumour necrosis factor-{alpha}

Submitted 1 August 2008; revised version accepted 30 January 2009.
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