title: Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate.
abstract: The hypothesis of the present work was that the pannus tissue overlying the articular hard tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We therefore 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 the pannocytes in the pannus-hard tissue junction. Inflammatory round cells associated with the critical interface contained TNF-alpha and IL-1beta. These cytokines induced collagenase-3 secretion in cultured rheumatoid synovial fibroblasts. Procollagenase-3 activators, stromelysin-1, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the pannus-hard tissue junction. Active collagenase-3 was inhibited with alendronate (IC50 = 500-750 microM). Collagenase-3, due to its substrate profile and local synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendronate, at concentrations attainable in vivo, is able to inhibit collagenase-3. This might offer an option to control collagenase-3-mediated tissue destruction in rheumatoid arthritis.
authors.affiliation: Department of Medicine, Helsinki University Central Hospital, Finland. yrjo.konttinen@helsinki.fi
authors.forename: Y T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: T
authors.initials: T
authors.lastname: Salo
authors.forename: R
authors.initials: R
authors.lastname: Hanemaaijer
authors.forename: H
authors.initials: H
authors.lastname: Valleala
authors.forename: T
authors.initials: T
authors.lastname: Sorsa
authors.forename: M
authors.initials: M
authors.lastname: Sutinen
authors.forename: A
authors.initials: A
authors.lastname: Ceponis
authors.forename: J W
authors.initials: JW
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Santavirta
authors.forename: O
authors.initials: O
authors.lastname: Teronen
authors.forename: C
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000328:Adult; D000368:Aged; D019386:Alendronate / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D017364:Collagenases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005122:Exudates and Transudates / Q000201:enzymology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D013583:Synovial Membrane / Q000201:enzymology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D019386:Alendronate