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Cleavage of cartilage oligomeric matrix protein (thrombospondin-5) by matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs

Dickinson, SC; Vankemmelbeke, MN; Buttle, DJ; Rosenberg, K; Heinegård, Dick LU and Hollander, AP (2003) In Matrix Biology 22(3). p.267-278
Abstract
Cartilage oligomeric matrix protein (COMP) is a pentameric glycoprotein present in cartilage, tendon and ligament. Fragments of the molecule are present in the diseased cartilage, synovial fluid and serum of patients with knee injuries, osteoarthritis and rheumatoid arthritis. Although COMP is a substrate for several matrix metalloprotemases (MMPs), the enzymes responsible for COMP degradation in vivo have yet to be identified. In this study we utilised well-established bovine cartilage culture models to examine IL-1alpha-stimulated COMP proteolysis in the presence and absence of MMP inhibitors. COMP was released from bovine nasal cartilage, in response to IL-1alpha, at an intermediate time between proteoglycans and type 11 collagen, when... (More)
Cartilage oligomeric matrix protein (COMP) is a pentameric glycoprotein present in cartilage, tendon and ligament. Fragments of the molecule are present in the diseased cartilage, synovial fluid and serum of patients with knee injuries, osteoarthritis and rheumatoid arthritis. Although COMP is a substrate for several matrix metalloprotemases (MMPs), the enzymes responsible for COMP degradation in vivo have yet to be identified. In this study we utilised well-established bovine cartilage culture models to examine IL-1alpha-stimulated COMP proteolysis in the presence and absence of MMP inhibitors. COMP was released from bovine nasal cartilage, in response to IL-1alpha, at an intermediate time between proteoglycans and type 11 collagen, when soluble MMP levels in the culture medium were undetectable. The major fragment of COMP released following IL-1alpha-stimulation migrated with an apparent molecular mass of approximately 110 kDa (Fragment-110) and co-migrated with both the major fragment present in human arthritic synovial fluid samples and the product of COMP cleavage by purified MMP-9. However, the broad-spectrum MMP and ADAM inhibitor BB94 only partially inhibited the formation of Fragment-110 and failed to inhibit COMP release significantly. Therefore the results of these studies indicate a role for proteinases other than MMPs in the degradation of COMP in bovine cartilage. It was further demonstrated that purified COMP was cleaved by ADAMTS-4, but not ADAMTS-I or -5, to yield a fragment which co-migrated with Fragment-110. Therefore this is the first demonstration of COMP as a substrate for ADAMTS-4, although it remains to be determined whether this enzyme plays a role in COMP degradation in vivo. (C) 2003 Elsevier Science B.V. and International Society of Matrix Biology. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aggrecanase, cartilage oligomeric matrix protein, ADAMTS, metalloproteinase, matrix
in
Matrix Biology
volume
22
issue
3
pages
267 - 278
publisher
Elsevier
external identifiers
  • wos:000184177700008
  • pmid:12853037
  • scopus:0038349637
ISSN
1569-1802
DOI
10.1016/S0945-053X(03)00034-9
language
English
LU publication?
yes
id
2d56d7e2-a34f-4c38-8367-5049881e4f68 (old id 305914)
date added to LUP
2007-08-29 12:03:24
date last changed
2018-11-21 20:43:44
@article{2d56d7e2-a34f-4c38-8367-5049881e4f68,
  abstract     = {Cartilage oligomeric matrix protein (COMP) is a pentameric glycoprotein present in cartilage, tendon and ligament. Fragments of the molecule are present in the diseased cartilage, synovial fluid and serum of patients with knee injuries, osteoarthritis and rheumatoid arthritis. Although COMP is a substrate for several matrix metalloprotemases (MMPs), the enzymes responsible for COMP degradation in vivo have yet to be identified. In this study we utilised well-established bovine cartilage culture models to examine IL-1alpha-stimulated COMP proteolysis in the presence and absence of MMP inhibitors. COMP was released from bovine nasal cartilage, in response to IL-1alpha, at an intermediate time between proteoglycans and type 11 collagen, when soluble MMP levels in the culture medium were undetectable. The major fragment of COMP released following IL-1alpha-stimulation migrated with an apparent molecular mass of approximately 110 kDa (Fragment-110) and co-migrated with both the major fragment present in human arthritic synovial fluid samples and the product of COMP cleavage by purified MMP-9. However, the broad-spectrum MMP and ADAM inhibitor BB94 only partially inhibited the formation of Fragment-110 and failed to inhibit COMP release significantly. Therefore the results of these studies indicate a role for proteinases other than MMPs in the degradation of COMP in bovine cartilage. It was further demonstrated that purified COMP was cleaved by ADAMTS-4, but not ADAMTS-I or -5, to yield a fragment which co-migrated with Fragment-110. Therefore this is the first demonstration of COMP as a substrate for ADAMTS-4, although it remains to be determined whether this enzyme plays a role in COMP degradation in vivo. (C) 2003 Elsevier Science B.V. and International Society of Matrix Biology. All rights reserved.},
  author       = {Dickinson, SC and Vankemmelbeke, MN and Buttle, DJ and Rosenberg, K and Heinegård, Dick and Hollander, AP},
  issn         = {1569-1802},
  keyword      = {aggrecanase,cartilage oligomeric matrix protein,ADAMTS,metalloproteinase,matrix},
  language     = {eng},
  number       = {3},
  pages        = {267--278},
  publisher    = {Elsevier},
  series       = {Matrix Biology},
  title        = {Cleavage of cartilage oligomeric matrix protein (thrombospondin-5) by matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs},
  url          = {http://dx.doi.org/10.1016/S0945-053X(03)00034-9},
  volume       = {22},
  year         = {2003},
}