Increased vulnerability of postarthritic cartilage to a second arthritic insult: accelerated MMP activity in a flare up of arthritis

Objective-Murine antigen induced arthritis (AIA) is a chronic, smouldering inflammation. Flares of arthritis can be induced by antigen rechallenge or exposure to inflammatory mediators like interleukin 1 (IL1). These flares a re characterised by a fast and marked proteoglycan (PG) depletion if compar ed with the initial arthritis. This study investigated the involvement of m etalloproteinases in both the initial and the flare phase of arthritis. Methods-Murine AIA was induced and a flare up of arthritis was induced by i njection of 10 ng of IL1 beta. Messenger RNA levels of MMP-1 and -3 were st udied by RT-PCR. MMP activity in cartilage, during both primary AIA as well as the flare up of arthritis, was studied by immunodetection of MMP specif ic neoepitopes in aggrecan (VDIPEN). Cartilage just before flare induction was analysed for presence of MMPs at the mRNA level as well as at the prote in level by zymography. Results-At the onset of AIA, a fast upregulation of mRNA for stromelysin an d collagenase was noted. However, no VDIPEN epitopes were detected during t his early phase of arthritis. They appeared when PG depletion was severe at day 7 of arthritis and disappeared when cartilage was repaired. IL1 inject ion into a knee joint at week 4 of ALA caused a flare up of arthritis, coin ciding with a fast and marked PG degradation. This degradation was characte rised by accelerated expression of VDIPEN epitopes if compared with the exp ression in primary AIA. Analysis of cartilage at week 4 of AIA showed still increased mRNA levels of MMP-1 and -3. Moreover, increased levels of laten t MMPs were present as well, as APMA activation induced profound VDIPEN epi tope. In vitro exposure to IL1 did show increased PG breakdown but no VDIPE N expression, suggesting that factors in addition to IL1 are needed to caus e the in vivo VDIPEN expression. Conclusions-The fast and marked PG depletion seen in a flare up of AIA coin cides with accelarated expression of MMP induced neoepitopes compared with expression during primary ALA. This accelerated expression is probably link ed to increased levels of latent enzyme, which were found to be present in the cartilage before induction of a flare up.