INCREASED SERUM CONCENTRATIONS OF CARTILAGE OLIGOMERIC MATRIX PROTEIN. A PROGNOSTIC MARKER IN EARLY RHEUMATOID ARTHRITIS

Two cartilage specific macromolecules, cartilage oligomericmatrix protein (COMP) and proteoglycan, were quantified by immunoassayin sera of two groups of patients with rheumatoid arthritis(RA) of recent onset to evaluate the prognostic value of suchmeasurements. Patients with rapidly progressive joint destructionhad increased COMP concentrations initially, which subsequentlydecreased. A group with more benign disease, and less extensivejoint damage, had normal COMP levels throughout the study period.Serum concentrations of proteoglycan were normal in both groups.Thus measurement of COMP in serum early in the course of RAholds promise as a prognostic marker for development of jointdestruction in this disease KEY WORDS: Non-collagenous cartilage matrix protein, Proteoglycan, Prognosis, Joint destruction     

Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions

Objective. To investigate whether fragmentation of proteoglycans in arthritis results in domains that have different levels of release from cartilage at different stages of the disease. Methods. Two regions of the proteoglycan, the hyaluronan-binding region and the glycosaminoglycanrich region of the core protein, were measured, by immunoassay, in knee joint synovial fluids of patients with rheumatoid arthritis or reactive arthritis. Results. Synovial fluid concentrations of the glycosaminoglycan-rich region were highest in rheumatoid arthritis patients who had little cartilage damage as determined by radiography, whereas release of the hyaluronan-binding region predominated in patients with advanced cartilage destruction. In reactive arthritis, release of the glycosaminoglycan-rich region predominated. Conclusion. These findings indicate that the hyaluronan-binding region is initially retained in the tissue during the development of cartilage destruction. The combined analysis of these markers offers a new avenue for assessment of the degree of cartilage damage in arthritis.     

Serum concentrations of hyaluronan and proteoglycan in joint disease. Lack of association.

Circulating hyaluronan originating from the synovial membrane and circulating proteoglycan released from cartilage were determined by specific assays in patients with osteoarthritis (OA), rheumatoid arthritis (RA), reactive arthritis or juvenile chronic arthritis (JCA). Elevated hyaluronan concentrations were found in OA and RA, suggesting proliferation of the synovial membrane in both diseases. The proteoglycan concentrations were highest in OA and polyarticular JCA indicating increased turnover of cartilage matrix. The concentrations of the macromolecules did not correlate except in the group with JCA. Serum concentrations of hyaluronan and proteoglycan thus differ between disease groups and may reflect different aspects of the arthritic process.     

Improvement of reduced serum cartilage oligomeric matrix protein levels in systemic juvenile idiopathic arthritis patients treated with the anti-interleukin-6 receptor monoclonal antibody tocilizumab

In this study, we determined serum cartilage oligomeric matrix protein (COMP) levels in systemic juvenile idiopathic arthritis (sJIA) patients during both the active and the remission phases to investigate how the growth cartilage turnover changed under tocilizumab treatment. Specimens were collected from 201 healthy children under 16 years of age with no growth impairment, and paired sera were collected from 11 sJIA patients treated with tocilizumab. Disease activity was assessed from white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and ferritin, and the COMP concentration was determined by sandwich enzyme-linked immunosorbent assay. Serum COMP concentrations were found independent of age, and the mean value in healthy children was 17.74 ± 5.6 U/L. The mean serum COMP in sJIA patients during the active phase was 10.75 ± 3.9 U/L, lower than that of healthy children. The mean serum COMP in the remission phase (14.89 ± 3.9 U/L) was significantly higher than that in the active period (P < 0.05). These results suggested that in sJIA patients, a reduced serum COMP concentration is a useful marker of active disease and growth impairment, and that the growth cartilage turnover suppressed during the active phase is improved in the remission phase under tocilizumab treatment.     

Serum concentrations of cartilage oligomeric matrix protein,fibrinogen and hyaluronan distinguish inflammation and cartilage destruction in experimental arthritis in rats

OBJECTIVES: We investigated if changes in serum/plasma fibrinogen (FIB), hyaluronan (HA) and cartilage oligomeric matrix protein (COMP) levels can be used to differentiate between inflammation and cartilage involvement during arthritis. METHODS: Collagen-induced arthritis (CIA), oil-induced arthritis (OIA) and for comparison, experimental autoimmune encephalitis (EAE) induced in DA rats were investigated. RESULTS: Elevations of FIB concentrations were apparent at days 4-7 post-immunization in both arthritis models reaching a maximum on day 20-21, i.e. before peak arthritis. Elevations of HA in both models were seen shortly before macroscopically apparent arthritis, and peaked at or just before maximal arthritis, i.e. later in CIA than in OIA. COMP levels increased only after onset of arthritis and peaked late in disease (days 34-37), being significantly higher in the more destructive CIA compared with the less destructive OIA. During EAE flares, only FIB levels increased. CONCLUSIONS: FIB is a general inflammation marker, HA appears to be a marker for synovitis and changes in COMP levels appear to reflect the cartilage destruction process.     

Clinical significance of decreased serum concentration of cartilage oligomeric matrix protein in systemic juvenile idiopathic arthritis

OBJECTIVE: Serum cartilage oligomeric matrix protein (COMP) concentration is elevated in patients with early osteoarthritis and early rheumatoid arthritis, and may be a biomarker of cartilage turnover. We investigated whether serum COMP concentration could be a clinically significant marker of arthritis and/or growth impairment in juvenile idiopathic arthritis (JIA). METHODS: Specimens were collected from 82 healthy blood donors under 22 years of age with no growth impairment who served as healthy controls, and from 24 patients with JIA (6 with oligoarthritis, 10 with polyarthritis, 8 with systemic JIA) presenting with active arthritis. Serum COMP concentration was determined using a human COMP assay kit. RESULTS: Serum COMP concentrations were significantly higher in all controls less than 16 years of age than in all controls aged 16 years or older. There was a significant negative correlation between serum COMP concentration and serum C-reactive protein in patients with JIA. Serum COMP concentrations in patients with systemic JIA were significantly lower than those in controls. CONCLUSION: Serum COMP concentrations in healthy children reflected increased cartilage turnover in the growth phase. Because the serum COMP concentration was decreased in cases of systemic JIA in which growth impairment was pronounced, the systemic inflammation occurring in systemic JIA may have an effect on cartilage turnover, which plays an important role in growth. Serum COMP concentration may prove to be a marker that indicates growth impairment in systemic JIA.     

Cartilage oligomeric matrix protein in serum and synovial fluid of rheumatoid arthritis: potential use as a marker for joint cartilage damage

Abstract

This study examined the serum and synovial fluid concentrations of cartilage oligomeric matrix protein (COMP) in relation to the evolution of joint cartilage damage and the requirement for surgery in 125 patients with rheumatoid arthritis (RA). We compared the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and matrix metalloproteinase-3 (MMP-3) levels with COMP levels determined by specific enzyme-linked immunosorbent assay (ELISA). Patients were divided into three groups: (1) patients with least erosive disease (LES); (2) patients with more erosive disease (MES); and (3) patients with mutilating disease (MUD). In addition, synovial fluid samples were collected from patients undergoing arthroscopic synovectomy of the knee joint (ASS) and total knee arthroplasty (TKA). Serum COMP levels correlated with the ESR (P < 0.0001, r = 0.374, n = 125) and the CRP level (P = 0.0014, r = 0.281, n = 125). COMP levels did not correlate with the MMP-3 level (P = 0.182, r = 0.114, n = 125). The COMP levels of the LES group were significantly lower than those of the MES or MUD groups. Lastly, synovial fluid COMP levels in the TKA group were higher than in the ASS group. Therefore, these findings suggest that serum and synovial fluid COMP levels in patients with RA may reflect cartilage destruction and are correlated with the ESR and the CRP level, which are indicators of the acute-phase response.     

Cartilage oligomeric matrix protein in serum and synovial fluid of rheumatoid arthritis: potential use as a marker for joint cartilage damage

This study examined the serum and synovial fluid concentrations of cartilage oligomeric matrix protein (COMP) in relation to the evolution of joint cartilage damage and the requirement for surgery in 125 patients with rheumatoid arthritis (RA). We compared the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and matrix metalloproteinase-3 (MMP-3) levels with COMP levels determined by specific enzyme-linked immunosorbent assay (ELISA). Patients were divided into three groups: (1) patients with least erosive disease (LES); (2) patients with more erosive disease (MES); and (3) patients with mutilating disease (MUD). In addition, synovial fluid samples were collected from patients undergoing arthroscopic synovectomy of the knee joint (ASS) and total knee arthroplasty (TKA). Serum COMP levels correlated with the ESR (P < 0.0001, r = 0.374, n = 125) and the CRP level (P = 0.0014, r = 0.281, n = 125). COMP levels did not correlate with the MMP-3 level (P = 0.182, r = 0.114, n = 125). The COMP levels of the LES group were significantly lower than those of the MES or MUD groups. Lastly, synovial fluid COMP levels in the TKA group were higher than in the ASS group. Therefore, these findings suggest that serum and synovial fluid COMP levels in patients with RA may reflect cartilage destruction and are correlated with the ESR and the CRP level, which are indicators of the acute-phase response.     

Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions.

OBJECTIVE. To investigate whether fragmentation of proteoglycans in arthritis results in domains that have different levels of release from cartilage at different stages of the disease. METHODS. Two regions of the proteoglycan, the hyaluronan-binding region and the glycosaminoglycan-rich region of the core protein, were measured, by immunoassay, in knee joint synovial fluids of patients with rheumatoid arthritis or reactive arthritis. RESULTS. Synovial fluid concentrations of the glycosaminoglycan-rich region were highest in rheumatoid arthritis patients who had little cartilage damage as determined by radiography, whereas release of the hyaluronan-binding region predominated in patients with advanced cartilage destruction. In reactive arthritis, release of the glycosaminoglycan-rich region predominated. CONCLUSION. These findings indicate that the hyaluronan-binding region is initially retained in the tissue during the development of cartilage destruction. The combined analysis of these markers offers a new avenue for assessment of the degree of cartilage damage in arthritis.     

Inhibition of cartilage proteoglycan release by a specific inactivator of cathepsin b and an inhibitor of matrix metalloproteinases. evidence for two converging pathways of chondrocyte-mediated proteoglycan degradation

Objective. To investigate mechanisms of cartilage matrix destruction by a study of the effects of a specific inactivator of cathepsin B and an inhibitor of several matrix metalloproteinases (MMP) on cartilage proteoglycan release. Methods. Cartilage explants were treated with either recombinant human interleukin-1α (rHuIL-1α) or retinoic acid in the presence or absence of the inhibitors, and proteoglycan release was quantitated. Tests for nonspecific effects of the inhibitors included reversibility, rates of protein synthesis and glycolysis, and effects on other rHuIL-1α–mediated events. Results. The cathepsin B inactivator inhibited rHuIL-1α–stimulated proteoglycan release at nanomolar concentrations, but failed to significantly inhibit retinoic acid–stimulated proteoglycan release. An inhibitor of MMP was inhibitory to both rHuIL-1α–stimulated release and retinoic acid–stimulated release. Conclusion. Cathepsin B is implicated in rHuIL-1α–stimulated loss of cartilage proteoglycan. Its lack of involvement in retinoic acid–stimulated proteoglycan release suggests the existence of at least 2 pathways of cartilage proteoglycan breakdown, which may converge at the activation of a matrix prometalloproteinase.     

Cartilage derived proteoglycans in body fluids of children. Inverse correlation with age

We have previously shown synovial fluid (SF) proteoglycan concentrations to be sensitive markers of altered cartilage metabolism in arthritis. We determined the proteoglycan concentrations in sera and SF from 23 patients with juvenile chronic arthritis and in sera from 30 healthy children by a specific enzyme linked immunosorbent assay. In both groups of children, decreasing concentrations of proteoglycans were seen during growth. Changes were most marked at the age of 12-13. The serum levels were higher in the healthy children. Our results suggest an age related metabolic change of articular cartilage, resulting in diminished release of proteoglycans to SF and blood with growing age up to 20 years. Measurement of proteoglycans could be a useful tool for studying this process.     

Release of cartilage and bone macromolecules into synovial fluid: differences between psoriatic arthritis and rheumatoid arthritis

OBJECTIVE: To elucidate whether differences in the destructive tissue process in cartilage and bone in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) can be recognised by different release patterns of molecular fragments derived from joint tissue. METHODS: Aggrecan, cartilage oligomeric matrix protein (COMP), and bone sialoprotein (BSP) were quantified by immunoassays in knee joint synovial fluid samples. These were obtained early in the disease course of patients with PsA and RA. At the time of arthrocentesis radiographs of their knee and hip joints were normal. RESULTS: At follow up no destruction had developed in the knees and hips of most patients with PsA (n=18), whereas the patients with RA could be separated into one "destructive" group (n=18) and one "non-destructive" group (n=25). Patients with PsA had low synovial fluid aggrecan concentrations (p<0.001 v the RA destructive group) but high COMP concentrations (p<0.01 and p<0.05 v destructive and non-destructive RA groups, respectively). Consequently, the aggrecan/COMP ratio was lowest in the PsA group (p<0.001 and p<0.01 v the destructive and non-destructive RA group, respectively). The synovial fluid concentrations of BSP did not differ between the three patient groups. CONCLUSIONS: The release pattern of aggrecan and COMP, reflecting cartilage turnover, differed between the PsA group and, particularly, the destructive RA group. This suggests that different pathophysiological mechanisms for cartilage involvement operate in these conditions, with different destructive potential. The BSP concentrations did not differ between the patients groups, which indicates similar levels of bone involvement.     

Increased pentosidine, an advanced glycation end product, in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein

BACKGROUND: Pentosidine, an advanced glycation end product, increasingly accumulates in articular cartilage with age, and contributes to the pathogenesis of osteoarthritis (OA). Increased pentosidine concentrations are associated with inflammatory disorders-for example, rheumatoid arthritis. OBJECTIVE: To compare pentosidine serum concentrations in patients with knee OA and in healthy volunteers and to determine a relationship between pentosidine and cartilage oligomeric matrix protein (COMP)-a marker of articular cartilage destruction. METHODS: Paired serum and synovial fluid samples were obtained by arthrocentesis from 38 patients with knee OA and from 38 healthy volunteers. Pentosidine concentration was measured by reverse phase high performance liquid chromatography with fluorescent detection and COMP was determined by sandwich ELISA. RESULTS: Significantly increased serum pentosidine (p<0.01) and COMP (p<0.05) levels were detected in the patients with OA compared with the control group. Serum pentosidine correlated significantly with synovial fluid pentosidine (p<0.001). Pentosidine in synovial fluid (p<0.05) and in serum (p<0.05) correlated significantly with synovial fluid COMP. Pentosidine and COMP concentrations did not correlate significantly with the radiological stage of the disease. CONCLUSION: Increased pentosidine serum concentration in patients with OA and its correlation with the cartilage destruction marker COMP in synovial fluid suggests that pentosidine may be important in OA pathology and is a new potential OA marker.     

Serum levels of cartilage oligomeric matrix protein (COMP): a rapid decrease in patients with active rheumatoid arthritis undergoing intravenous steroid treatment

To examine the influence of intravenous steroid-treatment (IST) on serum levels of Cartilage oligomeric matrix protein (COMP) in patients with active rheumatoid arthritis (RA). Serum levels of COMP and C-reactive protein (CRP) were measured in 12 patients with highly active RA (Steinbrocker stages II–IV) and in 5 patients with highly active reactive arthritis (ReA) (positive testing for HLA-B27) before starting daily IST. Patients received a total steroid dosage between 100 and 500 mg of prednisolone. COMP was measured by a commercially available sandwich-type ELISA-kit developed by AnaMar Medical AB, Sweden. Statistical evaluation was calculated by paired t test. In the RA group, COMP levels ranged from 6.3 to 19.4 U/l (mean 12.9 U/l), CRP from 5 to 195 mg/l (mean 77.8 mg/l), the COMP levels of the ReA group ranged from 5.1 to 7.4 U/l (mean 7.9 U/l), the CRP levels from 13 to 126 mg/l (mean 49 mg/l). We found a significant difference between the initial COMP levels in RA+ and ReA patients (P<0.005). In contrast to the ReA group, serum-COMP levels of RA+ patients (P<0.004) and the VAS (P<0.0001) decreased significantly within 2–10 days after the first treatment with steroids. The CRP levels remained unchanged in both groups. Our results indicate that the intravenous treatment with steroids in patients with highly active RA leads to a significant decrease of cartilage degradation. COMP seems to be a valuable parameter not even as a prognostic factor, but as a marker for monitoring the therapy response in patients with RA.     

Rheumatoid synovial fluid contains bioactive leukemia inhibitory factor with cartilage degrading activity--another target for chondroprotective intervention

OBJECTIVE: To determine if the procatabolic activity of inflammatory synovial fluids (SF) from patients with rheumatoid arthritis (RA) could be attenuated by the cytokine antagonists murine leukemia inhibitory factor (LIF) binding protein (mLBP) and interleukin 1 receptor antagonist (IL-1ra). METHODS: Pig articular cartilage explants were cultured in the presence of either 20% v/v rheumatoid (RA) or osteoarthritic (OA) SF and varying concentrations of either mLBP and/or IL-1ra. The catabolic activity of the SF and the relative effects of mLBP and/or IL-1ra were assessed by determining the percentage release of sulfated glycosaminoglycans from cartilage explants. LIF concentrations were measured by ELISA. RESULTS: RA SF but not OA SF stimulated release of proteoglycans from pig cartilage explants in vitro (47.3 +/- 2.2% vs 24.6 +/- 2.0%; p < 0.0001). Murine LBP at 100 ng/ml and recombinant human (rh) IL-1ra at 5000 ng/ml produced a dose dependent inhibition of this proteoglycan release (p < 0.0067 and p < 0.0111, respectively). The RA SF stimulated proteoglycan release was attenuated by mLBP and rhIL-1ra independently. No additive effect of this attenuation was observed when maximal inhibitory doses were used in combination. The decrease in proteoglycan release produced by mLBP correlated significantly with LIF concentrations in RA SF. CONCLUSION: These findings are consistent with the concept that IL-1 stimulates cartilage proteoglycan resorption in RA. They also support the hypothesis that LIF, too, contributes to cartilage proteoglycan resorption in RA. The residual stimulation not accounted for by IL-1 or LIF suggests other cytokines may contribute. The role of LIF and related or unrelated cytokines may need to be taken into account to optimize chondroprotection in RA and other rheumatic diseases.     

Corticosteroid treatment of experimental arthritis retards cartilage destruction as determined by histology and serum COMP

OBJECTIVE: To examine if changes in serum cartilage oligomeric matrix protein (COMP) correlate with the development of cartilage damage, as measured by histological grading, in corticosteroid-treated animals with collagen-induced arthritis (CIA). METHODS: DA rats with established CIA were treated with corticosteroids (betamethasone, 0.1 mg/kg body weight) or placebo (saline) intraperitoneally once daily after reaching an arthritis score exceeding 1. The treatment continued throughout the study. Arthritis progression was monitored by clinical scoring of paws, serial measurements of serum COMP and fibrinogen, and histological grading of paws. RESULTS: Corticosteroid treatment reduced clinical signs of arthritis compared with placebo (arthritis score reduced, P < 0.01 at day 25). Corticosteroid treatment also reduced fibrinogen levels compared with placebo (P < 0.01). The morphological changes in the joint were less severe in the corticosteroid-treated animals (median cartilage score 4 in the placebo group, 0 in the corticosteroid-treated group; P < 0.01). The levels of COMP remained unchanged during treatment in the corticosteroid-treated arthritic animals, whereas an increase in levels of COMP was observed in rats treated with placebo (P < 0.01). There was a correlation between serum COMP and the extent of cartilage destruction at day 25 after immunization (r = 0.77, P < 0.001). CONCLUSIONS: Corticosteroids given therapeutically to arthritic rats diminish joint destruction histologically, and stable serum COMP levels reflect this effect.     

Metalloproteinases,tissue inhibitor,and proteoglycan fragments in knee synovial fluid in human osteoarthritis

Objective. To determine the concentrations of human stromelysin-1, collagenase, tissue inhibitor of metalloproteinases (TIMP), and proteoglycan fragments in knee synovial fluid in patients with injury to the meniscus or anterior cruciate ligament, posttraumatic osteoarthritis, primary osteoarthritis, or pyrophosphate arthritis. Methods. Synovial fluid samples were collected from patients with knee disease diagnosed arthroscopically and radiologically. Concentrations of stromelysin-1, collagenase, and TIMP-1 were determined by sandwich immunoassay, using monoclonal and polyclonal antibodies. Fragments of cartilage proteoglycan containing the chondroitin sulfate-binding region were determined by immunoassay with a polyclonal antibody. Results. Average concentrations of metalloproteinases, TIMP, and proteoglycan fragments in joint fluid were significantly elevated in patients from all disease groups as compared with volunteers with healthy knees (reference group). Stromelysin concentrations in disease groups averaged 15–45 times that of the reference group. The molar ratios between stromelysin and collagenase varied between 10 and 150. The molar ratio between total stromelysin and free TIMP was 0.5 in the reference group and between 1.6 and 5.3 in the disease groups. Conclusion. Stromelysin concentration in joint fluid is a parameter that distinguishes diseased joints from healthy joints, with a sensitivity of 84% and a specificity of 90%. The high concentrations of metalloproteinase relative to TIMP in joint fluid from patients with the conditions studied may be associated with cartilage matrix degradation in these arthritides.     

CARTILAGE OLIGOMERIC MATRIX PROTEIN: A NOVEL MARKER OF CARTILAGE TURNOVER DETECTABLE IN SYNOVIAL FLUID AND BLOOD

Cartilage oligomeric matrix protein (COMP) is a tissue specificnon-collagenous matrix protein. We have developed an enzyme-linkedimmunosorbent assay for the detection of this protein in synovialfluid and serum. The protein has been quantified in these fluidsin patients with rheumatoid arthritis (RA), reactive arthritis,juvenile chronic arthritis, osteoarthritis and in sera of controlsubjects. The protein was detectable in all fluids and the synovialfluid levels were always higher than in serum in paired samples.The highest knee joint synovial fluid levels were found in reactivearthritis patients and the lowest in RA patients with advanceddestruction of the knee joint. However, the relative synovialfluid content of COMP was higher in these RA patients than inpatients with advanced osteoarthritis. In patients with longstandingreactive synovitis the concentrations decreased. This decrease,however, was less marked than for proteoglycan concentrations. The serum concentrations were low in patients with juvenilechronic arthritis and in patients with RA with advanced cartilagedestruction of the studied knee joint. In the other groups serumlevels did not differ between groups or from controls. KEY WORDS: Cartilage matrix, Noncollagenous protein, Rheumatoid arthritis, Proteoglycans     

Inhibitory effects of leflunomide therapy on the activity of matrixmetalloproteinase-9 and the release of cartilage oligomeric matrix protein in patients with rheumatoid arthritis

OBJECTIVE: To determine the effects of the disease modifying antirheumatic drug (DMARD) leflunomide on the expression of the matrix metalloproteinase MMP-1 (collagenase) and the activity of MMP-9 that are believed to play a major role in cartilage destruction associated with inflammation in patients with rheumatoid arthritis (RA). Serum concentrations of cartilage oligomeric matrix protein (COMP) should offer promise for monitoring tissue degradation in the RA joints during a 6-month therapy with leflunomide. METHODS: Thirty-six patients with RA meeting the ACR-criteria were recruited for the study in a multicentre trial. A dose of 20 mg leflunomide/day (after a 3-day 100 mg/day loading dose), an isoxazole derivate and inhibitor of the "de novo" pyrimidine synthesis, was administered for a study period of 6 months. MMP-1, the activity of MMP-9 and COMP values were measured in serum by enzyme immuno assay. The very sensitive acute phase protein serum amyloid A (SAA) was also determined by EIA. The measurements were performed before and after 3 and 6 months of leflunomide therapy. RESULTS: High levels of active MMP-9, COMP and SAA were detected in the sera of the patients with RA prior to the start of the leflunomide therapy compared to normal control sera. A significant reduction of the MMP-9 activity levels was seen after 3 months immunomodulation with leflunomide and was maintained after 6 months (p < 0.01). The degradation marker COMP and the inflammation marker SAA decreased significantly after 6 months (p < 0.04, respectively p < 0.01). There was also an insignificant tendency of MMP-1 reduction in serum after 6 months. CONCLUSION: This study demonstrated that a DMARD therapy with leflunomide can cause positive effects on cartilage degradation and inflammation achieving reductions in the acute phase protein SAA, the enzymatic attack of MMPs and the loss of the cartilage matrix component COMP.     

Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis

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 disease, such as rheumatoid arthritis (RA) and osteoarthritis (OA). This study was undertaken to investigate the ability of COMP to regulate complement, a capacity that has previously been shown for some other cartilage proteins.

Methods

Regulation of complement by COMP was studied using functional in vitro assays. Inter‐actions between complement proteins and COMP were investigated by direct binding assay and electron microscopy. Circulating COMP and COMP–C3b complexes in serum and synovial fluid from RA and OA patients and healthy controls were measured with a novel enzyme‐linked immunosorbent assay.

Results

We found in vivo evidence of complement activation by released COMP in the general circulation of patients with RA, but not patients with OA. COMP induced activation and deposition of C3b and C9 specifically via the alternative pathway of complement, which was attributable to direct interaction between COMP and properdin. Furthermore, COMP inhibited 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 in inflammation has been demonstrated in vivo. 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.