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Adenovirus mediated intra-articular expression of collagenase-3 (MMP-13) induces inflammatory arthritis in mice

K Joronen¹, R Ala-aho², M-L Majuri³, H Alenius³, V-M Kähäri², E Vuorio¹

¹ Skeletal Research Programme, Department of Medical Biochemistry and Molecular Biology, University of Turku, Finland
² Department of Dermatology, Turku University Central Hospital and Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
³ Finnish Institute for Occupational Health, Helsinki, Finland

Correspondence to:
Correspondence to:
Dr E Vuorio
Department of Medical Biochemistry and Molecular Biology, University of Turku, FIN-20520 Turku, Finland; eero.vuorio{at}utu.fi

Objectives: To better understand the role of collagenase-3 (MMP-13) in joint inflammation by investigating the consequences of transient overexpression of human collagenase-3 (matrix metalloproteinase-13 (MMP-13)), introduced by adenoviral gene delivery, in the mouse knee joint.

Methods: A single dose (5x10⁷ pfu) of recombinant adenovirus coding either for ß-galactosidase (RAdLacZ) or human MMP-13 (RAdMMP-13) was injected intra-articularly into the knee joint of adult mice. The joints were analysed at frequent intervals up to 4 weeks by histology, immunohistochemistry, and RNA analysis.

Results: When RAdLacZ reporter virus was used, adenoviruses efficiently infected synovial cells, chondrocytes of articular cartilage, and hypertrophic chondrocytes of the growth plate. The infection was transient as no reporter gene activity was detected 3 weeks after the injection. After RAdMMP-13 injection into the knee joints, expression of human MMP-13 in joint tissues resulted in an arthritis characterised by recruitment of inflammatory cells and increased production of cytokines and chemokines, synovial hyperplasia, and pannus formation. After the loss of MMP-13 transgene expression at 3 weeks, these inflammatory changes began to diminish.

Conclusions: MMP-13 has a role in the onset of inflammatory reaction in synovium. However, damage to articular cartilage was only rarely detected after the short term overexpression of MMP-13.

Keywords: arthritis; matrix metalloproteinases; adenovirus; inflammation; mice

Abbreviations: FGF, fibroblast growth factor; IL, interleukin; MMP, matrix metalloproteinase; PBS, phosphate buffered saline; RAdLacZ, recombinant adenovirus coding for ß-galactosidase; RadMMP-13, recombinant adenovirus coding for MMP-13; RT-PCR, reverse transcriptase-polymerase chain reaction; TC, threshold cycle; TNF, tumour necrosis factor

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