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 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.
Konttinen
Y T
YT
Department of Medicine, Helsinki University Central Hospital, Finland. yrjo.konttinen@helsinki.fi
Salo
T
T
Hanemaaijer
R
R
Valleala
H
H
Sorsa
T
T
Sutinen
M
M
Ceponis
A
A
Xu
J W
JW
Santavirta
S
S
Teronen
O
O
López-Otín
C
C
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
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