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A novel paradigm for dendritic cells as effectors of cartilage destruction

Lookup NU author(s): Dr Rachel Lakey, Emeritus Professor Drew Rowan, Professor John IsaacsORCiD, Emeritus Professor Tim Cawston, Professor Catharien HilkensORCiD

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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- 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- 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-. Our data suggest a potential important role for mDC-derived TNF- in RA, which is in line with the previously reported observations that DCs are a major source of TNF- in early autoimmune lesions and that anti-TNF- 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.

Publication metadata

Author(s): Lakey RL, Morgan TG, Rowan AD, Isaacs JD, Cawston TE, Hilkens CM

Publication type: Article

Publication status: Published

Journal: Rheumatology

Year: 2009

Volume: 48

Issue: 5

Pages: 502-7

ISSN (print): 0080-2727

ISSN (electronic): 1662-3959

Publisher: S. Karger AG

URL: http://dx.doi.org/10.1093/rheumatology/kep040

DOI: 10.1093/rheumatology/kep040

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