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. Our results suggest that CD44 participates in a variety of cell-cell and cell-matrix interactions at the site of inflammation. CD44- and HA-mediated events in inflammatory synovitis are current not understood. CD44 is present on synovial cells, and HA is a major constituent of synovial fluid and extracellular matrix in the normal joint. However, the amounts of CD44 and HA increase dramatically 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 HA molecules that are poorly associated with matrix and diffuse into the extracellular space thus 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 the production of IL-1 and TNF-alpha by synovial cells is augmented by HA. Furthermore, CD44 and HA appear to be associated with the invasion of articular cartilage by rheumatoid pannus. In this study, we will compare synovial tissues and cells from normal and inflamed joints, in both murine and human systems, with respect to the molecular and functional properties of HA and CD44. We will delineate some of the regulatory and signaling mechanisms which may contribute to persistent leukocyte and synovial fibroblast activation. We also intend to determine if abnormal cell-matrix and cell-cell interactions in the rheumatoid synovium can be corrected by modulating CD44 function. The results of in vitro experiments will be conveyed to in vivo studies 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 CD44- and HA-mediated events in arthritic processes, and open new avenues for therapeutic intervention in rheumatoid arthritis.
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