title: NC4 Domain of 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.
abstract: Collagen IX containing the N-terminal noncollagenous domain 4 (NC4) is unique to cartilage and a member of the family of fibril-associated collagens with both collagenous and noncollagenous 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, 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 polymerization 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 are important parts of a machinery that protects the cartilage from complement activation and chronic inflammation seen in diseases like rheumatoid arthritis.
authors.affiliation: Department of Laboratory Medicine, Section of Medical Protein Chemistry, Lund University, S-205 02 Malmö, Sweden.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Kalchishkova
authors.forename: Camilla Melin
authors.initials: CM
authors.lastname: Fürst
authors.forename: Dick
authors.initials: D
authors.lastname: Heinegård
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000737:chemistry / Q000378:metabolism*; D024081:Collagen Type IX / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation / Q000502:physiology; D003179:Complement C3b / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015935:Complement C4b / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050716:Complement C4b-Binding Protein; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015938:Complement Membrane Attack Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071235:Fibromodulin; D057809:HEK293 Cells; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C055609:C4BPA protein, human; D024081:Collagen Type IX; D050716:Complement C4b-Binding Protein; D015938:Complement Membrane Attack Complex; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D006649:Histocompatibility Antigens; D011509:Proteoglycans; C113360:osteoadherin; D000071235:Fibromodulin; D003179:Complement C3b; D015935:Complement C4b; D017242:Complement Factor H