title: The C-type lectin of the aggrecan G3 domain activates complement.
abstract: Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint.
authors.affiliation: Department of Laboratory Medicine, Division of Medical Protein Chemistry, Lund University, Malmö, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Melin Fürst
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Kasper
authors.initials: K
authors.lastname: Vadstrup
authors.forename: Dick
authors.initials: D
authors.lastname: Heinegård
authors.forename: Anders
authors.initials: A
authors.lastname: Aspberg
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D053674:Aggrecans / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002356:Cartilage / Q000737:chemistry / Q000276:immunology; D002417:Cattle; D002460:Cell Line; D003167:Complement Activation / Q000276:immunology*; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000276:immunology; D003171:Complement Pathway, Classical / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000276:immunology*
chemical_list: D053674:Aggrecans; D015922:Complement C1q; D017242:Complement Factor H; D003165:Complement System Proteins