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Cleavage of fibromodulin in cartilage explants involves removal of the N-terminal tyrosine sulphate rich region by proteolysis at a site that is sensitive to MMP-13.

Heathfield, Terrence LU ; Önnerfjord, Patrik LU ; Dahlberg, Leif LU and Heinegård, Dick LU (2004) In Journal of Biological Chemistry 279(8). p.6286-6295
Abstract
Integrity of cartilage fails in joint disease. The current work aimed to identify candidate active proteinases in joint diseases using an in vitro model for cartilage degradation induced by interleukin-1. A critical event in the process of cartilage destruction in joint disease is the failure of the collagen fiber network to maintain integrity. Proteins binding to the surface of the fibers are likely early points of failure. Fibromodulin, a member of the leucine-rich repeat protein family, is one predominant protein in cartilage and is known for its roles in the formation of collagen fibrils and sustained interaction with these formed fibers. Cleavage removes the tyrosine sulfate-rich region in the N terminus of fibromodulin. Whereas... (More)
Integrity of cartilage fails in joint disease. The current work aimed to identify candidate active proteinases in joint diseases using an in vitro model for cartilage degradation induced by interleukin-1. A critical event in the process of cartilage destruction in joint disease is the failure of the collagen fiber network to maintain integrity. Proteins binding to the surface of the fibers are likely early points of failure. Fibromodulin, a member of the leucine-rich repeat protein family, is one predominant protein in cartilage and is known for its roles in the formation of collagen fibrils and sustained interaction with these formed fibers. Cleavage removes the tyrosine sulfate-rich region in the N terminus of fibromodulin. Whereas fibromodulin bound to collagen in tissue was digested, purified fibromodulin was not cleaved. In contrast an N-terminal 10-kDa fragment, Gln19-Lys98, of the protein generated by Lys-C digestion contains the cleavage site and was a substrate cleaved by the enzyme in medium from stimulated cultures. In solution, digestion of this substrate with matrix metalloproteinase (MMP)-2, -9, -8, and -13 demonstrated that only MMP-13 was capable to efficiently cleave it. The cleavage product obtained after MMP-13 digestion was identical to that observed in cleaved fibromodulin from cartilage explant cultures stimulated with interleukin-1. MMP-13 treatment of fresh articular cartilage also produced the fragment under study. The elucidation of the enzyme responsible for such cleavage may lead to treatment modalities involving its selective inhibition for patients suffering from arthritis. The known structure of the fragments permits the generation of neo-epitope antibodies to the cleavage site, which can be used to detect ongoing cartilage degradation in patients with arthritic disease, an important adjunct in monitoring disease progression, active disease, and efficacy of treatment. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
279
issue
8
pages
6286 - 6295
publisher
ASBMB
external identifiers
  • wos:000188969200013
  • pmid:14660626
  • scopus:1342346601
ISSN
1083-351X
DOI
10.1074/jbc.M307765200
language
English
LU publication?
yes
id
195c8bb8-375f-43fe-85e2-04f8e593e25c (old id 119739)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14660626&dopt=Abstract
date added to LUP
2007-07-12 15:59:01
date last changed
2017-10-22 03:47:39
@article{195c8bb8-375f-43fe-85e2-04f8e593e25c,
  abstract     = {Integrity of cartilage fails in joint disease. The current work aimed to identify candidate active proteinases in joint diseases using an in vitro model for cartilage degradation induced by interleukin-1. A critical event in the process of cartilage destruction in joint disease is the failure of the collagen fiber network to maintain integrity. Proteins binding to the surface of the fibers are likely early points of failure. Fibromodulin, a member of the leucine-rich repeat protein family, is one predominant protein in cartilage and is known for its roles in the formation of collagen fibrils and sustained interaction with these formed fibers. Cleavage removes the tyrosine sulfate-rich region in the N terminus of fibromodulin. Whereas fibromodulin bound to collagen in tissue was digested, purified fibromodulin was not cleaved. In contrast an N-terminal 10-kDa fragment, Gln19-Lys98, of the protein generated by Lys-C digestion contains the cleavage site and was a substrate cleaved by the enzyme in medium from stimulated cultures. In solution, digestion of this substrate with matrix metalloproteinase (MMP)-2, -9, -8, and -13 demonstrated that only MMP-13 was capable to efficiently cleave it. The cleavage product obtained after MMP-13 digestion was identical to that observed in cleaved fibromodulin from cartilage explant cultures stimulated with interleukin-1. MMP-13 treatment of fresh articular cartilage also produced the fragment under study. The elucidation of the enzyme responsible for such cleavage may lead to treatment modalities involving its selective inhibition for patients suffering from arthritis. The known structure of the fragments permits the generation of neo-epitope antibodies to the cleavage site, which can be used to detect ongoing cartilage degradation in patients with arthritic disease, an important adjunct in monitoring disease progression, active disease, and efficacy of treatment.},
  author       = {Heathfield, Terrence and Önnerfjord, Patrik and Dahlberg, Leif and Heinegård, Dick},
  issn         = {1083-351X},
  language     = {eng},
  number       = {8},
  pages        = {6286--6295},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Cleavage of fibromodulin in cartilage explants involves removal of the N-terminal tyrosine sulphate rich region by proteolysis at a site that is sensitive to MMP-13.},
  url          = {http://dx.doi.org/10.1074/jbc.M307765200},
  volume       = {279},
  year         = {2004},
}