TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors.
Aggrecanases are considered to play a key role in the destruction of articular cartilage during the progression of arthritis. Here we report that the N-terminal inhibitory domain of tissue inhibitor of metalloproteinases 3 (N-TIMP-3), but not TIMP-1 or TIMP-2, inhibits glycosaminoglycan release from bovine nasal and porcine articular cartilage explants stimulated with interleukin-1alpha or retinoic acid in a dose-dependent manner. This inhibition is due to the blocking of aggrecanase activity induced by the catabolic factors. Little apoptosis of primary porcine chondrocytes is observed at an effective concentration of N-TIMP-3. These results suggest that TIMP-3 may be a candidate agent for use against cartilage degradation.
Gendron
Christi
C
Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, W6 8LH, London, UK.
Kashiwagi
Masahide
M
Hughes
Clare
C
Caterson
Bruce
B
Nagase
Hideaki
H
D053674:Aggrecans; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D046508:Culture Techniques; D010450:Endopeptidases / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D037181:Lectins, C-Type; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D007375:Interleukin-1; D037181:Lectins, C-Type; D011480:Protease Inhibitors; D011509:Proteoglycans; D011994:Recombinant Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D014212:Tretinoin; D010450:Endopeptidases; C083641:aggrecanase