Inhibition of interleukin-1alpha-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid.
OBJECTIVE
To determine whether matrix metalloproteinases (MMPs) degrade cartilage oligomeric matrix protein (COMP) to produce fragments similar to those found in synovial fluid (SF) from patients with arthritis.


METHODS
COMP fragments were generated in vitro by treating (a) bovine articular cartilage with interleukin-1alpha (IL-1alpha), (b) purified bovine COMP with MMPs, and (c) articular cartilage with MMPs. The fragments generated in each case were analyzed by Western blot, using an antibody to the C-terminal heptadecapeptide of COMP.


RESULTS
IL-1alpha stimulation of cartilage resulted in a fragmentation of COMP, which was inhibited by MMP inhibitors CGS 27023A and BB-94. Isolated, recombinant MMPs rapidly degraded purified COMP, as well as COMP residing in cartilage. Several COMP fragments produced in vitro had similar electrophoretic mobility to those in SF of patients with arthritis.


CONCLUSIONS
MMPs may contribute to the COMP fragments found in vivo. Quantitation of MMP-specific fragments may be useful in the evaluation of MMP inhibitors in patients with arthritis.
Ganu
V
V
Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
Goldberg
R
R
Peppard
J
J
Rediske
J
J
Melton
R
R
Hu
S I
SI
Wang
W
W
Duvander
C
C
Heinegård
D
D
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001168:Arthritis / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002358:Cartilage, Articular / Q000737:chemistry; D002417:Cattle; D017364:Collagenases / Q000378:metabolism / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000276:immunology / Q000378:metabolism*; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D064235:Matrilin Proteins; D020781:Matrix Metalloproteinase 1; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D010003:Osteoarthritis / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D013582:Synovial Fluid / Q000737:chemistry / Q000378:metabolism
D000906:Antibodies; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D007375:Interleukin-1; D064235:Matrilin Proteins; D010446:Peptide Fragments; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1