Rheumatoid synovial fibroblasts (or synoviocytes) localized to the cartilage-pannus junction mediate the? destruction of articular and/or surrounding connective tissues. While increased attention has begun to focus? on the ability of RA synoviocytes to express matrix-destructive enzymes belonging to either the matrix? metalloproteinase or cysteine proteinase gene families, the precise role that these enzymes play in the? synoviocyte-mediated dissolution and/or invasion of cartilage, ligaments or tendons remains undefined. With? regard to the matrix metalloproteinase (MMP) gene family, RA synoviocytes are known to express a complex? mix of secreted and membrane-anchored MMPs, but the identity of the subset of enzymes involved in type? I collagen degradation (the major extracellular matrix components of ligaments/tendons and cartilage,? respectively) has not been clarified. Likewise, though RA synoviocytes can express a number of? collagenolytic cysteine proteinases, these acidophilic enzymes are normally confined to the lysosomal? compartment and the ability of the intact cells to secrete these enzymes into the extracellular milieu is? unclear. Based on recent studies which demonstrate that i),membrane-anchored MMPs may play critical? roles in regulating the invasive activity of neoplastic cells through collagen-rich tissues and ii) that cysteine? proteinases can mediate tissue-destructive effects when secreted into pericellular acidic microenvironments? generated by vacuolar-type H+-ATPase, we propose that rheumatoid synoviocytes use these two groups of? proteinases to degrade and/or invade affected tissues. To this end, we propose to i) identify the major type? I/I I collagenolytic systems in RA synoviocytes, ii) characterize the cysteine proteinase-secretory potential of? RA synoviocytes and the regulation of these proteinases by the vacuolar-type H+-ATPase and iii) determine? the role of these systems in controlling RA synoviocyte-mediated cartilage degradation and invasion in vitro? and in vivo.? The ability of RA synoviocytes to destroy cartilage, tendons and ligaments leads to irreversible tissue? damage and much of the disease-associated morbidity. The identification of the destructive processes by? which RA synoviocytes mediate these effects will not only provide new insights into this disease process, but? also may lead to the identification of important new targets for therapeutic intervention.
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