| 41. |
- Halasz, Krisztina, et al.
(författare)
-
COMP acts as a catalyst in collagen fibrillogenesis
- 2007
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 282:43, s. 31166-31173
-
Tidskriftsartikel (refereegranskat)abstract
- We have previously reported that COMP (cartilage oligomeric matrix protein) is prominent in cartilage but is also present in tendon and binds to collagens I and II with high affinity. Here we show that COMP influences the fibril formation of these collagens. Fibril formation in the presence of pentameric COMP was much faster, and the amount of collagen in fibrillar form was markedly increased. Monomeric COMP, lacking the N-terminal coiled-coil linker domain, decelerated fibrillogenesis. The data show that stimulation of collagen fibrillogenesis depends on the pentameric nature of COMP and not only on collagen binding. COMP interacts primarily with free collagen I and II molecules, bringing several molecules to close proximity, apparently promoting further assembly. These assemblies further join in discrete steps to a narrow distribution of completed fibril diameters of 149 +/- 16 nm with a banding pattern of 67 nm. COMP is not found associated with the mature fibril and dissociates from the collagen molecules or their early assemblies. However, a few COMP molecules are found bound to more loosely associated molecules at the tip/end of the growing fibril. Thus, COMP appears to catalyze the fibril formation by promoting early association of collagen molecules leading to increased rate of fibrillogenesis and more distinct organization of the fibrils.
|
|
| 42. |
- Hansson, Ann-Sofie, et al.
(författare)
-
Relapsing polychondritis, induced in mice with matrilin 1, is an antibody- and complement-dependent disease
- 2004
-
Ingår i: American Journal of Pathology. - New York, NY : Elsevier. - 0002-9440 .- 1525-2191. ; 164:3, s. 959-966
-
Tidskriftsartikel (refereegranskat)abstract
- Relapsing polychondritis is an autoimmune disease that affects cartilage in the ear, nose, and respiratory tract. A pathogenic immune response has been proposed and antibodies to several cartilage proteins are detected in sera from these patients. To investigate the role of the humoral immune response in relapsing polychondritis, we used the matrilin-1-induced relapsing polychondritis model. Mice deficient of B cells (muMT) and mice congenic at the complement factor 5, were immunized with matrilin-1, a cartilage-specific protein mainly detected in the tracheal cartilage. To investigate the binding properties and tissue selection of matrilin-1-specific antibodies we produced matrilin-1-specific B-cell hybridomas. Although 83% of the micro MT heterozygous mice developed respiratory distress and erosive chondritis in the respiratory tract, none of the B-cell-deficient mice were susceptible to disease. In addition, we show that complement factor 5 is important for the induction of matrilin-1-induced relapsing polychondritis. Monoclonal matrilin-1-specific antibodies injected into neonatal mice bound specifically to cartilage of the respiratory tract and adult B-cell-deficient mice injected with the same antibodies developed erosive chondritis in the respiratory tract. We conclude that relapsing polychondritis can be mediated by a pathway involving tissue-specific antibodies and complement activation.
|
|
| 43. |
|
|
| 44. |
- Happonen, Kaisa, et al.
(författare)
-
COMP-C3b Complexes in Rheumatoid Arthritis with Severe Extraarticular Manifestations
- 2013
-
Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 40:12, s. 2001-2005
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate biomarker patterns in rheumatoid arthritis (RA) with extraarticular manifestations. Methods. Cartilage oligomeric matrix protein (COMP), COMP-C3b, and soluble terminal complement complexes (sTCC) were measured by ELISA. Results. COMP-C3b levels were higher in patients with RA than in healthy controls and lower in extraarticular RA (ExRA) than in RA controls. In patients with ExRA, sTCC levels were higher than in RA controls, and correlated inversely with serum COMP-C3b levels in the ExRA group. Conclusion. Patients with ExRA had lower levels of COMP-C3b. This may be a consequence of complement consumption or a lower potential for COMP from these patients to activate complement.
|
|
| 45. |
- Happonen, Kaisa, et al.
(författare)
-
Complement inhibitor C4b-binding protein interacts directly with small glycoproteins of the extracellular matrix.
- 2009
-
Ingår i: Journal of immunology. - 1550-6606. ; 182:3, s. 1518-1525
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 46. |
|
|
| 47. |
- Happonen, Kaisa, et al.
(författare)
-
Interactions of the complement system with molecules of extracellular matrix: Relevance for joint diseases.
- 2012
-
Ingår i: Immunobiology. - : Elsevier BV. - 1878-3279 .- 0171-2985. ; 217:11, s. 1088-1096
-
Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly disabling disease affecting all structures of the joint. Understanding the pathology behind the development of RA is essential for developing targeted therapeutic strategies as well as for developing novel markers to predict disease onset. Several molecules normally hidden within the cartilage tissue are exposed to complement components in the synovial fluid upon cartilage breakdown. Some of these have been shown to activate complement and toll-like receptors, which may enhance an already existing inflammatory response, thereby worsening the course of disease. Other cartilage-resident molecules have in contrast shown to possess complement-inhibitory properties. Knowledge about mechanisms behind pathological complement activation in the joints will hopefully lead to methods which allow us to distinguish patients with pathological complement activation from those where other inflammatory pathways are predominant. This will help to elucidate which patients will benefit from complement inhibitory therapies, which are thought to aid a specific subset of patients or patients at a certain stage of disease. Future challenges are to target the complement inhibition specifically to the joints to minimize systemic complement blockade.
|
|
| 48. |
- Happonen, Kaisa, et al.
(författare)
-
PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex
- 2012
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 287:11, s. 8092-8100
-
Tidskriftsartikel (refereegranskat)abstract
- PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and already formed C5b-8, but inhibits C9 polymerization thereby preventing formation of the lytic pore. The alternative pathway is moreover inhibited already at the level of C3-convertase formation due to an interaction between PRELP and C3. This suggests that PRELP may down-regulate complement attack at basement membranes and on damaged cartilage and therefore limit pathological complement activation in inflammatory disease such as RA. The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins.
|
|
| 49. |
- Happonen, Kaisa, et al.
(författare)
-
Regulation of complement by COMP allows for a novel molecular diagnostic principle in rheumatoid arthritis.
- 2010
-
Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 62:12, s. 3574-3583
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:: Cartilage oligomeric matrix protein (COMP) is a structural component of cartilage where it catalyzes collagen fibrillogenesis. Elevated amounts of COMP are found in serum during increased turnover of cartilage associated with active joint diseases, such as rheumatoid arthritis (RA) and osteoarthritis (OA). In this study we investigated the ability of COMP to regulate complement. Such capacity was previously shown for some cartilage proteins. METHODS:: Regulation of complement by COMP was studied using functional assays in vitro. Interactions between complement proteins and COMP were investigated using direct binding assays and electron microscopy. Circulating COMP and COMP-C3b complexes in serum and synovial fluid from RA and OA patients and healthy controls were measured using a novel ELISA. RESULTS:: We show in vivo evidence of complement activation by released COMP in the general circulation of patients with RA, but not OA patients. We found that COMP induces activation and deposition of C3b and C9 specifically via the alternative pathway of complement, which is attributable to a direct interaction between COMP and properdin. Furthermore, COMP inhibits the classical and the lectin complement pathways due to direct interaction with the stalk region of C1q and mannose-binding lectin, respectively. CONCLUSION:: COMP is the first extracellular matrix protein for which an active role is demonstrated in inflammation in vivo where it can activate one complement pathway at the same time as it has the potential to inhibit another. The net outcome of these interactions is most likely determined by the type of released COMP-fragments, which may be disease-specific.
|
|
| 50. |
- Happonen, Kaisa, et al.
(författare)
-
Serum COMP-C3b complexes in rheumatic diseases and relation to anti-TNF-alpha treatment
- 2012
-
Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Cartilage oligomeric matrix protein (COMP) is found at elevated concentrations in sera of patients with joint diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). We recently showed that COMP activates complement via the alternative pathway and that COMP-C3b complexes are present in sera of RA patients, but not in healthy controls. We now set out to elaborate on the information provided by this marker in a variety of diseases and larger patient cohorts. Methods: COMP-C3b levels in sera were measured by using an enzyme-linked immunosorbent assay (ELISA) capturing COMP and detecting C3b. Serum COMP was measured by using ELISA. Results: COMP-C3b levels were significantly elevated in patients with RA as well as in systemic lupus erythematosus (SLE), compared with healthy controls. SLE patients with arthritis had significantly higher COMP-C3b levels than did those without. COMP-C3b was furthermore elevated in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, systemic sclerosis, and OA. COMP-C3b did not correlate with COMP in any of the patient groups. COMP-C3b correlated with disease activity in RA, but not in other diseases. COMP-C3b levels in RA patients decreased on treatment with tumor necrosis factor (TNF)-alpha inhibitors, whereas the levels increased in patients with AS or PsA. The changes of COMP-C3b did not parallel the changes of C-reactive protein (CRP). Conclusions: COMP-C3b levels are elevated in several rheumatologic diseases and correlate with inflammatory measures in RA. COMP-C3b levels in RA decrease during TNF-alpha inhibition differently from those of CRP, suggesting that formation of COMP-C3b relates to disease features not reflected by general inflammation measures.
|
|
