The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q.
Components that propagate inflammation in joint disease may be derived from cartilage since the inflammation resolves after joint replacement. We found that the cartilage component fibromodulin has the ability to activate an inflammatory cascade, i.e. complement. Fibromodulin and immunoglobulins cause comparable deposition of C1q, C4b, and C3b from human serum. Using C1q and factor B-deficient sera in combination with varying contents of metal ions, we established that fibromodulin activates both the classical and the alternative pathways of complement. Further studies revealed that fibromodulin binds directly to the globular heads of C1q, leading to activation of C1. However, deposition of the membrane attack complex and C5a release were lower in the presence of fibromodulin as compared with IgG. This can be explained by the fact that fibromodulin also binds complement inhibitor factor H. Factor H and C1q bind to non-overlapping sites on fibromodulin, but none of the interactions is mediated by the negatively charged keratan sulfate substituents of fibromodulin. C1q but not factor H binds to an N-terminal fragment of fibromodulin previously implicated to be affected in cartilage stimulated with the inflammatory cytokine interleukin 1. Taken together our observations indicate fibromodulin as one factor involved in the sustained inflammation of the joint.
Sjöberg
Andreas
A
Department of Laboratory Medicine, University Hospital Malmö, BMC, Lund University, Sweden.
Onnerfjord
Patrik
P
Mörgelin
Matthias
M
Heinegård
Dick
D
Blom
Anna M
AM
D003167:Complement Activation; D015922:Complement C1q / Q000737:chemistry* / Q000378:metabolism; D003165:Complement System Proteins; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000737:chemistry*; D000071235:Fibromodulin; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007249:Inflammation; D007375:Interleukin-1 / Q000737:chemistry; D007477:Ions; D007632:Keratan Sulfate / Q000737:chemistry; D008854:Microscopy, Electron; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry*; D020349:Surface Plasmon Resonance; D013997:Time Factors
D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D007074:Immunoglobulin G; D007375:Interleukin-1; D007477:Ions; D011509:Proteoglycans; D000071235:Fibromodulin; D015922:Complement C1q; D003165:Complement System Proteins; D007632:Keratan Sulfate