Rheumatoid synovial fibroblasts (or synoviocytes) localized to the cartilage-pannus junction mediate thedestruction of articular and/or surrounding connective tissues. While increased attention has begun to focuson the ability of RA synoviocytes to express matrix-destructive enzymes belonging to either the matrixmetalloproteinase or cysteine proteinase gene families, the precise role that these enzymes play in thesynoviocyte-mediated dissolution and/or invasion of cartilage, ligaments or tendons remains undefined. Withregard to the matrix metalloproteinase (MMP) gene family, RA synoviocytes are known to express a complexmix of secreted and membrane-anchored MMPs, but the identity of the subset of enzymes involved in typeI 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 ofcollagenolytic cysteine proteinases, these acidophilic enzymes are normally confined to the lysosomalcompartment and the ability of the intact cells to secrete these enzymes into the extracellular milieu isunclear. Based on recent studies which demonstrate that i),membrane-anchored MMPs may play criticalroles in regulating the invasive activity of neoplastic cells through collagen-rich tissues and ii) that cysteineproteinases can mediate tissue-destructive effects when secreted into pericellular acidic microenvironmentsgenerated by vacuolar-type H+-ATPase, we propose that rheumatoid synoviocytes use these two groups ofproteinases to degrade and/or invade affected tissues. To this end, we propose to i) identify the major typeI/I I collagenolytic systems in RA synoviocytes, ii) characterize the cysteine proteinase-secretory potential ofRA synoviocytes and the regulation of these proteinases by the vacuolar-type H+-ATPase and iii) determinethe role of these systems in controlling RA synoviocyte-mediated cartilage degradation and invasion in vitroand in vivo.The ability of RA synoviocytes to destroy cartilage, tendons and ligaments leads to irreversible tissuedamage and much of the disease-associated morbidity. The identification of the destructive processes bywhich RA synoviocytes mediate these effects will not only provide new insights into this disease process, butalso may lead to the identification of important new targets for therapeutic intervention.
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