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The NC4 domain of the cartilage-specific collagen IX inhibits complement directly due to attenuation of membrane attack formation and indirectly through binding and enhancing activity of complement inhibitors C4B-binding protein and factor H.

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Author

  • Nikolina Kalchishkova
  • Camilla Melin Fürst
  • Dick Heinegård
  • Anna Blom

Summary, in English

Collagen IX containing the N-terminal non-collagenous domain 4 (NC4) domain is unique to cartilage and a member of the family of fibril-associated collagens with both collagenous and non-collagenous domains. Collagen IX is located at the surface of fibrils formed by collagen II and a minor proportion of collagen XI, playing roles in tissue stability and integrity. The NC4 domain projects out from the fibril surface and provides sites for interaction with other matrix components such as cartilage oligomeric matrix protein (COMP), matrilins, fibromodulin and osteoadherin. Fragmentation of collagen IX and loss of the NC4 domain are early events in cartilage degradation in joint diseases that precedes major damage of collagen II fibrils. Our results demonstrate that NC4 can function as a novel inhibitor of the complement system able to bind C4, C3 and C9, and to directly inhibit C9 polymerisation and assembly of the lytic membrane attack complex. NC4 also binds the complement inhibitors C4b-binding protein and factor H and enhances their cofactor activity in degradation of activated complement components C4b and C3b. NC4 interactions with fibromodulin and osteoadherin inhibited binding to C1q and complement activation by these proteins. Taken together our results suggest that collagen IX and its interactions with matrix components is an important part of a machinery that protects the cartilage from complement activation and chronic inflammation seen in diseases like rheumatoid arthritis.

Publishing year

2011

Language

English

Pages

27915-27926

Publication/Series

Journal of Biological Chemistry

Volume

286

Issue

32

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Other Basic Medicine
  • Other Clinical Medicine

Status

Published

Research group

  • Protein Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 1083-351X