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

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 (5 x 10(7) pfu) of recombinant adenovirus coding either for beta-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.