P2:RA Synovial Fibroblasts, matrix destructive enzymes

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

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