Collagen degradation induced by the combination of IL-1alpha and plasminogen in rabbit articular cartilage explant culture.
To investigate the effect of plasminogen on cartilage catabolism, we assessed collagen degradation in rabbit articular cartilage explants treated with or without plasminogen and interleukin-1alpha (IL-1alpha). The combination of IL-1 alpha and plasminogen induced rapid collagen degradation, amounting to more than 60% of the total collagen by day 7, while neither IL-1alpha nor plasminogen alone had any effect. To examine the mechanism of collagen degradation induced by IL-1alpha and plasminogen, the matrix metalloproteinases (MMPs) in the culture supernatants were examined by ELISA, Western blotting and gelatin zymography. We found that the treatment with IL-1alpha induced MMP-1, MMP-3, and MMP-9. In addition, plasminogen converted the pro form of MMPs into the active form. Both a tissue inhibitor of metalloproteinases-1 (TIMP-1) and a synthetic hydroxamate MMP inhibitor prevented this collagen release. These results suggest that plasminogen causes collagen degradation via activation of MMPs induced by IL-1alpha.
Saito
S
S
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki.
Katoh
M
M
Masumoto
M
M
Matsumoto
S
S
Masuho
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D002356:Cartilage / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D003094:Collagen / Q000187:drug effects / Q000378:metabolism*; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism; D046508:Culture Techniques; D004359:Drug Therapy, Combination; D004586:Electrophoresis / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D005780:Gelatin / Q000737:chemistry / Q000378:metabolism; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011817:Rabbits; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D005780:Gelatin; D010958:Plasminogen; D003094:Collagen; D017364:Collagenases; D018093:Gelatinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1