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The extracellular matrix and inflammation - Fibromodulin activates the classical pathway of complement by directly binding C1q

Holmér, Andreas LU ; Önnerfjord, Patrik LU ; Mörgelin, Matthias LU ; Heinegård, Dick LU and Blom, Anna LU (2005) In Journal of Biological Chemistry 280(37). p.32301-32308
Abstract
Components that propagate inflammation in joint disease may be derived from cartilage since the inflammation resolves after joint replacement. We found that the cartilage component fibromodulin has the ability to activate an inflammatory cascade, i.e. complement. Fibromodulin and immunoglobulins cause comparable deposition of C1q, C4b, and C3b from human serum. Using C1q and factor B-deficient sera in combination with varying contents of metal ions, we established that fibromodulin activates both the classical and the alternative pathways of complement. Further studies revealed that fibromodulin binds directly to the globular heads of C1q, leading to activation of C1. However, deposition of the membrane attack complex and C5a release were... (More)
Components that propagate inflammation in joint disease may be derived from cartilage since the inflammation resolves after joint replacement. We found that the cartilage component fibromodulin has the ability to activate an inflammatory cascade, i.e. complement. Fibromodulin and immunoglobulins cause comparable deposition of C1q, C4b, and C3b from human serum. Using C1q and factor B-deficient sera in combination with varying contents of metal ions, we established that fibromodulin activates both the classical and the alternative pathways of complement. Further studies revealed that fibromodulin binds directly to the globular heads of C1q, leading to activation of C1. However, deposition of the membrane attack complex and C5a release were lower in the presence of fibromodulin as compared with IgG. This can be explained by the fact that fibromodulin also binds complement inhibitor factor H. Factor H and C1q bind to non-overlapping sites on fibromodulin, but none of the interactions is mediated by the negatively charged keratan sulfate substituents of fibromodulin. C1q but not factor H binds to an N-terminal fragment of fibromodulin previously implicated to be affected in cartilage stimulated with the inflammatory cytokine interleukin 1. Taken together our observations indicate fibromodulin as one factor involved in the sustained inflammation of the joint. (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
280
issue
37
pages
32301 - 32308
publisher
ASBMB
external identifiers
  • wos:000231794800033
  • scopus:25444482114
ISSN
1083-351X
DOI
10.1074/jbc.M504828200
language
English
LU publication?
yes
id
2a9468de-e612-4510-819c-b552c53c4d88 (old id 224125)
date added to LUP
2007-10-05 14:42:27
date last changed
2017-10-22 03:54:00
@article{2a9468de-e612-4510-819c-b552c53c4d88,
  abstract     = {Components that propagate inflammation in joint disease may be derived from cartilage since the inflammation resolves after joint replacement. We found that the cartilage component fibromodulin has the ability to activate an inflammatory cascade, i.e. complement. Fibromodulin and immunoglobulins cause comparable deposition of C1q, C4b, and C3b from human serum. Using C1q and factor B-deficient sera in combination with varying contents of metal ions, we established that fibromodulin activates both the classical and the alternative pathways of complement. Further studies revealed that fibromodulin binds directly to the globular heads of C1q, leading to activation of C1. However, deposition of the membrane attack complex and C5a release were lower in the presence of fibromodulin as compared with IgG. This can be explained by the fact that fibromodulin also binds complement inhibitor factor H. Factor H and C1q bind to non-overlapping sites on fibromodulin, but none of the interactions is mediated by the negatively charged keratan sulfate substituents of fibromodulin. C1q but not factor H binds to an N-terminal fragment of fibromodulin previously implicated to be affected in cartilage stimulated with the inflammatory cytokine interleukin 1. Taken together our observations indicate fibromodulin as one factor involved in the sustained inflammation of the joint.},
  author       = {Holmér, Andreas and Önnerfjord, Patrik and Mörgelin, Matthias and Heinegård, Dick and Blom, Anna},
  issn         = {1083-351X},
  language     = {eng},
  number       = {37},
  pages        = {32301--32308},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {The extracellular matrix and inflammation - Fibromodulin activates the classical pathway of complement by directly binding C1q},
  url          = {http://dx.doi.org/10.1074/jbc.M504828200},
  volume       = {280},
  year         = {2005},
}