IDENTIFICATION OF MEMBRANE-TYPE 1 MATRIX METALLOPROTEINASE AS A NOVEL THERAPEUTIC TARGET OF RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose key pathological features is destruction of joint tissues including cartilage. Our recent data indicated that a cell membrane-anchored protein degrading enzyme termed, MT1-MMP, plays an essential role in cartilage erosion in RA. We hypothesize that specific inhibition of MT1-MMP can be a potential RA treatment. We propose to address this by assessing the effect of MT1-MMP inhibition in RA progression in a collagen-induced arthritis (CIA) in transgenic mice that express a dominant negative inhibitor of MT1-MMP. We will also analyze the effect of a MT1-MMP-specific inhibitory antibody in mice with CIA. Completing the proposed work would establish MT1-MMP as a novel therapeutic target of RA treatment, which may lead into development of novel RA therapy in the future.

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose key pathological features is destruction of joint tissues by inflamed synovial pannus tissue leading to a loss of joint function. We have recently discovered that one of the membrane-anchored matrix metalloproteinases (MT-MMPs), MT1-MMP, plays an essential role in promoting pannus invasion into cartilage in RA. MT1-MMP is highly expressed in the synovial cells forming a cartilage invasion front and inhibition of MT1-MMP effectively abrogates synovial cell invasion into cartilage matrix. MT1-MMP has also been shown to be an important molecule in the process of angiogenesis, as well as monocyte endothelial transmigration, both of which are essential steps in RA progression. Therefore, we hypothesize that specific inhibition of MT1-MMP can be a potential therapeutic intervention for RA treatment. To test the effect of MT1-MMP inhibition in RA progression, we have developed useful tools: transgenic mice that express a dominant negative form of MT1-MMP in fibroblasts and an MT1-MMP-specific inhibitory antibody. We will challenge the transgenic mice with collagen-induced arthritis (CIA) to examine the role of MT1-MMP in synovial fibroblasts during development of arthritis in vivo. We will also administer the MT1-MMP inhibitory antibody to mice with CIA in order to examine the role of MT1-MMP in broader cell populations during RA development, including endothelial cells and macrophages. Completing the proposed work would establish MT1-MMP as a novel therapeutic target of RA treatment, which may lead into development of novel RA therapy in the future.