Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate

The hypothesis of the present work was that the pannus tissue: overlying th e articular hard tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We th erefore analyzed the eventual presence of collagenase-3 and its regulation at the pannus-cartilage junction. Collagenase-3 mRNA (in situ hybridization ) and enzyme protein (ABC and immunofluorescence staining) were found in th e pannocytes in the pannus-hard tissue junction. Inflammatory round cells a ssociated with the critical interface contained TNF-alpha and IL-1 beta. Th ese cytokines induced collagenase-3 secretion in cultured rheumatoid synovi al fibroblasts. Procollagenase-3 activators, stromelysin-l, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the pann us-hard tissue junction. Active collagenase-3 was inhibited with alendronat e (IC50 = 500-750 mu M). Collagenase-3, due to its substrate profile and lo cal synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendron ate, at concentrations attainable in vivo, is able to inhibit collagenase-3 . This might offer an option to control collagenase-3-mediated tissue destr uction in rheumatoid arthritis. (C) 1999 Elsevier Science B.V./Internationa l Society of Matrix Biology. All right reserved.