This research proposal concerns the role of the hyaluronan (HA) receptor CD44, in synovial pathology during rheumatoid synovitis. We have demonstrated in mice with proteoglycan- and collagen-induced arthritis, that a monoclonal anti-CD44 antibody eliminates joint swelling and inflammatory leukocyte infiltration. These results suggest that CD44 and HA are important for adhesive interactions among synovial cells and leukocytes during joint inflammation. CD44 and HA are also utilized during the invasion of articular cartilage by rheumatoid pannus. CD44- and HA-mediated events in inflammatory synovitis, however, are poorly understood. CD44 is present on synovial cells and HA is a constituent of extracellular matrix in the normal joint, however, their amounts increase during inflammatory processes. Rheumatoid synovial cells and activated leukocytes express CD44 variant isoforms that are not detected in normal synovium. In contrast to normal joints, rheumatoid synovial tissue produces large amounts of HA which are poorly associated with matrix and diffuse into periarticular tissues, effecting joint swelling. Leukocytes, via the CD44-HA interaction, can be recruited and activated by HA present in the interstitial compartment of synovial tissue. Our preliminary results suggest that, in addition to HA, leukocyte CD44 is capable of recognizing another ligand which is expressed by synovial cells of arthritic joints. In this study we will compare normal and rheumatoid synovial cells, in both murine and human systems, with respect to HA binding and matrix metabolism, and determine if abnormal synoviocyte-matrix interactions displayed by rheumatoid synovial cells, can be corrected by modulating CD44 function. We will identify the synovial protein which may serve as a ligand for leukocyte CD44, and could be potentially used as a target for anti-inflammatory therapy. The results of in vitro experiments will be conveyed to in vivo studies on a murine model of inflammatory arthritis, and also on a chimeric model of destructive synovitis, utilizing human rheumatoid synovium and cartilage engrafted into SCID mice. We believe that the findings of the studies proposed here will provide a better understanding of the pathological roles of CD44- and HA-driven events in arthritic processes, and open new avenues for therapeutic intervention in rheumatoid arthritis.
