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* Department of Laboratory Medicine, Wallenberg Laboratory, University Hospital Malmö, Lund University, Malmö, Sweden; and
Department of Infection Medicine and
Department of Experimental Medical Science, Biomedical Center, Lund University, Lund, Sweden
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants from the Swedish Research Council, the Swedish Foundation for Strategic Research, the National Institutes of Health, King Gustav V’s 80th Anniversary Foundation, the Foundations of Österlund, Kock, Knut and Alice Wallenberg, and Inga-Britt and Arne Lundberg, and research grants from the University Hospitals in Malmö and Lund.
2 Address correspondence and reprint requests to Prof. Anna M. Blom, Department of Laboratory Medicine, Wallenberg Laboratory, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden. E-mail address: anna.blom{at}med.lu.se
3 Abbreviations used in this paper: C4BP, C4b-binding protein; CCP, complement control protein (domain); CHAD, chondroadherin; CRP, C-reactive protein; FH, factor H; FI, factor I; FM, fibromodulin; NHS, normal human serum; OPD, o-phenylenediamine; OSAD, osteoadherin; PRELP, proline arginine-rich end leucine-rich repeat protein; PS, protein S; RT, room temperature; SLRP, small leucine-rich repeat protein.
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