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Complement inhibitor C4b-binding protein interacts directly with small glycoproteins of the extracellular matrix.

Happonen, Kaisa LU ; Holmér, Andreas LU ; Mörgelin, Matthias LU ; Heinegård, Dick LU and Blom, Anna LU (2009) In Journal of immunology (Baltimore, Md. : 1950) 182(3). p.1518-1525
Abstract
Components derived from cartilage have been suggested to maintain the inflammation in joints in arthritis. Small leucine-rich repeat proteins (SLRPs) are structural components of cartilage important in organizing the meshwork of extracellular matrix components. It has recently been shown that the SLRP fibromodulin interacts with complement initiator C1q, leading to complement activation. The complement response is limited since fibromodulin also interacts with the complement inhibitor factor H. We have now found that osteoadherin, chondroadherin, fibromodulin, and proline arginine-rich end leucine-rich repeat protein bind to the complement inhibitor C4b-binding protein (C4BP). Using direct binding assays with C4BP fragments and C4BP... (More)
Components derived from cartilage have been suggested to maintain the inflammation in joints in arthritis. Small leucine-rich repeat proteins (SLRPs) are structural components of cartilage important in organizing the meshwork of extracellular matrix components. It has recently been shown that the SLRP fibromodulin interacts with complement initiator C1q, leading to complement activation. The complement response is limited since fibromodulin also interacts with the complement inhibitor factor H. We have now found that osteoadherin, chondroadherin, fibromodulin, and proline arginine-rich end leucine-rich repeat protein bind to the complement inhibitor C4b-binding protein (C4BP). Using direct binding assays with C4BP fragments and C4BP mutants lacking individual domains in combination with electron microscopy, we have demonstrated that mainly the central core of C4BP mediated binding to SLRPs. Binding of SLRPs to C4BP did not affect its ability to inhibit complement. Osteoadherin, fibromodulin, and chondroadherin, which bind C1q and activate complement, were found to cause significantly higher C9 deposition in C4BP-depleted serum compared with Igs, indicating that the level of complement activation initiated by SLRPs is regulated by simultaneous binding to C4BP. A similar dual binding of C1q and complement inhibitors was observed previously for other endogenous ligands (amyloid, prions, C-reactive protein, and apoptotic cells) but not for exogenous activators (bacteria-bound Igs). These interactions can be significant during inflammatory joint diseases, such as rheumatoid arthritis, where cartilage is degraded, and cartilage components are released into synovial fluid, where they can interact with factors of the complement system. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of immunology (Baltimore, Md. : 1950)
volume
182
issue
3
pages
1518 - 1525
publisher
American Association of Immunologists
external identifiers
  • WOS:000262842100036
  • PMID:19155499
  • Scopus:63149095644
ISSN
1550-6606
language
English
LU publication?
yes
id
976ec250-f8eb-4f2e-8f37-ecb3c8e83a3f (old id 1289483)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19155499?dopt=Abstract
date added to LUP
2009-02-04 13:01:59
date last changed
2016-11-01 10:16:40
@misc{976ec250-f8eb-4f2e-8f37-ecb3c8e83a3f,
  abstract     = {Components derived from cartilage have been suggested to maintain the inflammation in joints in arthritis. Small leucine-rich repeat proteins (SLRPs) are structural components of cartilage important in organizing the meshwork of extracellular matrix components. It has recently been shown that the SLRP fibromodulin interacts with complement initiator C1q, leading to complement activation. The complement response is limited since fibromodulin also interacts with the complement inhibitor factor H. We have now found that osteoadherin, chondroadherin, fibromodulin, and proline arginine-rich end leucine-rich repeat protein bind to the complement inhibitor C4b-binding protein (C4BP). Using direct binding assays with C4BP fragments and C4BP mutants lacking individual domains in combination with electron microscopy, we have demonstrated that mainly the central core of C4BP mediated binding to SLRPs. Binding of SLRPs to C4BP did not affect its ability to inhibit complement. Osteoadherin, fibromodulin, and chondroadherin, which bind C1q and activate complement, were found to cause significantly higher C9 deposition in C4BP-depleted serum compared with Igs, indicating that the level of complement activation initiated by SLRPs is regulated by simultaneous binding to C4BP. A similar dual binding of C1q and complement inhibitors was observed previously for other endogenous ligands (amyloid, prions, C-reactive protein, and apoptotic cells) but not for exogenous activators (bacteria-bound Igs). These interactions can be significant during inflammatory joint diseases, such as rheumatoid arthritis, where cartilage is degraded, and cartilage components are released into synovial fluid, where they can interact with factors of the complement system.},
  author       = {Happonen, Kaisa and Holmér, Andreas and Mörgelin, Matthias and Heinegård, Dick and Blom, Anna},
  issn         = {1550-6606},
  language     = {eng},
  number       = {3},
  pages        = {1518--1525},
  publisher    = {ARRAY(0xb91c378)},
  series       = {Journal of immunology (Baltimore, Md. : 1950)},
  title        = {Complement inhibitor C4b-binding protein interacts directly with small glycoproteins of the extracellular matrix.},
  volume       = {182},
  year         = {2009},
}