Active matrix metalloproteinases are present in cartilage during immune complex-mediated arthritis: A pivotal role for stromelysin-1 in cartilage destruction

The involvement of immune complexes during experimental arthritis in induct ion of metalloproteinases (MMP)-induced neoepitopes in aggrecan in cartilag e, as well as the role of stromelysin-1 (SLN-1) in the induction of this ne oepitope, was investigated. Passive immune complex arthritis was induced, a nd generation of the MMP-specific cleavage product (VDIPEN) was studied by immunolocalization. The role of SLN-1 was studied with use of SLN-1-deficie nt (SLN-1KO) mice. VDIPEN expression was studied in vitro by exposing the c artilage to IL-1 and subsequent activation of latent MMPs. Immune complex a rthritis was characterized by an acute inflammation, with influx of mainly polymorphonuclear cells into the joint cavity. Expression of VDIPEN neoepit opes was consistently found in areas extensively depleted from proteoglycan s. SLN-1KO mice did not show expression of the VDIPEN neoepitope, although inflammation and proteoglycan depletion was comparable to wild-type mice. I n addition, erosions of cartilage were absent in SLN-1KO mice, but were pre sent in wild-type mice, suggesting an important role for SLN-1 in cartilage destruction. In vitro studies showed that SLN-1 is also pivotally involved in IL-1-induced MMP activity. Stimulated polymorphonuclear neutrophils wer e able to activate latent MMPs present in the cartilage. Neutrophil elastas e was also capable of activating IL-1-induced latent MMPs, which identifies elastase as a possible activator for latent VDIPEN-inducing MMPs. This stu dy suggests that IC are important in the activation of latent MMPs in carti lage, possibly through polymorphonuclear neutrophil activation on the carti lage edge. SLN-1 is a pivotal enzyme in overall MMP-activity in cartilage d uring immune complex-mediated arthritis.