The Extracellular Matrix and Inflammation

Abstract

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.The complement system forms the core of the innate immune system and is organized in three different routes depending on initiating agent such as antibodies (classical pathway) or certain carbohydrates (lectin pathway). The alternative pathway is started by autoactivation of unstable complement factor C3 (1) and its subsequent binding to a surface lacking complement inhibitors, mainly factor H (FH).2 FH is able to protect self-surfaces where it is localized due to its ability to bind sialic acid and heparan sulfate (2). The main event of complement activation is formation of enzymatic complexes such as C3 and C5 convertases, which leads to release of anaphylatoxins C5a and C3a (3) and deposition of C3-fragments that are recognized by phagocytes (4). The final stage is the formation of the membrane attack complex (MAC). The control of this powerful system is maintained by a number of soluble or membrane-bound inhibitory proteins. Most inhibitors such as FH act on C3 and C5 convertases either by increasing the dissociation of enzyme complexes or by promoting degradation of C3b or C4b by the serine proteinase factor I.The physiological relevance of complement is demonstrated by recurrent infections when there are deficiencies of complement components and central involvement of the system in systemic lupus erythematosus and glomerulonephritis (5). However, complement resembles a double-edged sword as it also contributes to the pathogenesis of ischemic injury, rheumatoid arthritis, multiple sclerosis, and many more diseases (6). It appears that the undesirable side effects of complement are mainly due to excessive activation or activation initiated by erroneous molecu...

The Factor H Variant Associated with Age-related Macular Degeneration (His-384) and the Non-disease-associated Form Bind Differentially to C-reactive Protein, Fibromodulin, DNA, and Necrotic Cells

“…It was previously reported that FMOD binds C1q, which leads to complement activation (21). FMOD also binds FH, causing inhibition of the alternative pathway and thus a decrease in membrane attack complex formation (21). In the latter case, it is not clear which parts of the two molecules are involved in the interaction, although binding to C1q and FH, respectively, appears to engage different sites on FMOD.…”

“…Phosphorylcholine-bovine serum albumin (PC-BSA) was prepared by coupling p-aminophenyl-phosphorylcholine to bovine serum albumin according to the procedure described by Padilla et al (26). Deglycosylated FMOD was prepared by treatment with N-glycosidase F (Roche Applied Science) as previously described (21).…”

“…An additional anionic domain is in the N-terminal region, containing up to nine tyrosine sulfate residues (41,42). It was previously reported that FMOD binds C1q, which leads to complement activation (21). FMOD also binds FH, causing inhibition of the alternative pathway and thus a decrease in membrane attack complex formation (21).…”

“…Other ligands of FH, such as DNA (20) and the extracellular matrix proteoglycan fibromodulin (FMOD) (21), could potentially also bind at this site. Here we show that the His-384 variant of FH binds CRP less efficiently than the non-disease-associated form.…”

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

“…A large body of evidence shows that complement contributes to the development of RA in man and experimental animals (5). It has been shown that fibromodulin (FM) and osteoadherin (OSAD), constituents of the extracellular matrix, activate complement via the classical pathway and may enhance inflammation in joint disease (6,7). Fragments of these cartilage components are released by proteases during cartilage destruction to come in contact with complement in synovial fluid.…”