Biomedical subjects

H K Ronday

Publications and source records attributed to H K Ronday.

At least 19 recordsLinked to original sources

PubMed2006

Using internet technology to deliver a home-based physical activity intervention for patients with rheumatoid arthritis: A randomized controlled trial.

OBJECTIVE: To compare the effectiveness of 2 Internet-based physical activity interventions for patients with rheumatoid arthritis (RA). METHODS: A total of 160 physically inactive patients with RA who had a computer with Internet access were randomly assigned to an Internet-based physical activity program with individual guidance, a bicycle ergometer, and group contacts (individualized training [IT] group; n = 82) or to an Internet-based program providing only general information on exercises and physical activity (general training [GT] group; n = 78). Outcome measures included quantity of physical activity (questionnaire and activity monitor), functional ability, quality of life, and disease activity (baseline, 3, 6, 9, and 12 months). RESULTS: The proportion of physically active patients was significantly greater in the IT than in the GT group at 6 (38% versus 22%) and 9 months (35% versus 11%; both P < 0.05) regarding a moderate intensity level for 30 minutes in succession on at least 5 days a week, and at 6 (35% versus 13%), 9 (40% versus 14%), and 12 months (34% versus 10%; all P < 0.005) regarding a vigorous intensity level for 20 minutes in succession on at least 3 days a week. In general, there were no statistically significant differences regarding changes in physical activity as measured with an activity monitor, functional ability, quality of life, or disease activity. CONCLUSION: An Internet-based physical activity intervention with individually tailored supervision, exercise equipment, and group contacts is more effective with respect to the proportion of patients who report meeting physical activity recommendations than an Internet-based program without these additional elements in patients with RA. No differences were found regarding the total amount of physical activity measured with an activity monitor.

Activities of Daily Living↗

PubMed2006

Engagement and satisfaction with an Internet-based physical activity intervention in patients with rheumatoid arthritis.

OBJECTIVE: To assess the engagement in and satisfaction with an Internet-mediated physical activity intervention with individual supervision in patients with rheumatoid arthritis (RA). METHODS: The intervention studied was one of the two strategies aimed at enhancing physical activity in RA patients that were being compared in a randomized controlled trial. A total of 82 patients, all experienced in using Internet and e-mail and registered at three different rheumatology out-patient clinics, were randomly allocated to the Internet-mediated individualized intervention (52 weeks). They had access to personal physical activity schedules and received individual supervision by a physical therapist by means of weekly e-mail feedback. In addition, telephone contacts, an online discussion forum, six face-to-face group meetings and electronic newsletters were offered. Besides registration of returned physical activity schedules, engagement and satisfaction were measured through questionnaires. RESULTS: The median physical activity schedule return rate of the 82 participants was 55%. The mean number of patients logging into the website at least once a week was 53 (70%) over 12 months. Of all patients, 69 returned the questionnaires (response 84%). Telephone contacts were used by 38/67 patients (57%), the mean (SD) number of attended group meetings was 3.1 (1.5) and the discussion forum comprised 15 posted messages. Overall, the proportions of patients being (very) satisfied with the amount of e-mail contacts, telephone contacts, usefulness of website information, physical activity schedules, group meetings and website layout were >/=85%. A smaller proportion of patients were satisfied with the links to other websites (68%), the newsletters (55%) and the online discussion forum (32%). CONCLUSION: Physical activity schedules with weekly feedback by e-mail, telephone contacts and a limited number of group meetings were frequently used website tools and modes of communication of an Internet-based physical activity intervention, with high-satisfaction rates from RA patients. Discussion forum and newsletters were less used and appreciated. Caution should be taken when extrapolating the results found to groups of patients who are not experienced Internet and e-mail users or patients with more severe physical disabilities.

Adult↗

PubMed2005

Manual therapy in osteoarthritis of the hip: outcome in subgroups of patients.

OBJECTIVE: To investigate whether manual therapy has particular benefit in subgroups of patients defined on the basis of hip function, range of joint motion, pain and radiological deterioration. METHODS: The study was performed in the out-patient clinic of physical therapy of a large hospital. Data on 109 patients with OA of the hip (clinical ACR criteria) participating in a randomized clinical trial on the effects of manual therapy were used. The outcomes for hip function (Harris hip score), range of joint motion (ROM) and pain (VAS) were compared for specific subgroups. Subgroups were assigned by the median split method. The interaction effect between subgroup and treatment was tested using multiple regression analysis. RESULTS: No differences were observed in the effect of manual therapy in specific subgroups of patients defined on the basis of baseline levels of hip function, pain and ROM. On the basis of radiological grading of osteoarthritis (OA), we found that patients with severe radiological grading of OA had significantly worse outcome on ROM as a result of manual therapy than patients with mild or moderate radiological grading of OA. CONCLUSION: A significant interaction effect was found for only 1 out of 12 hypotheses investigated. Therefore, we conclude that there is no evidence for the particular benefit of manual therapy in subgroups of patients.

Aged↗

PubMed2005

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial.

OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

Antibodies, Monoclonal↗

PubMed2004

High intensity exercise or conventional exercise for patients with rheumatoid arthritis? Outcome expectations of patients, rheumatologists, and physiotherapists.

OBJECTIVE: To examine the outcome expectations of RA patients, rheumatologists, and physiotherapists regarding high intensity exercise programmes compared with conventional exercise programmes. METHODS: An exercise outcome expectations questionnaire was administered to 807 RA patients, 153 rheumatologists, and 624 physiotherapists. The questionnaire consisted of four statements regarding positive and negative outcomes of high intensity exercise programmes and four similar statements for conventional exercise programmes. A total expectation score for both conventional and high intensity exercise was calculated, ranging from -2 (very negative expectation) to 2 (very positive expectation). RESULTS: The questionnaire was returned by 662 RA patients (82%), 132 rheumatologists (86%), and 467 physiotherapists (75%). The mean (95% confidence interval) scores for high intensity exercise programmes were 0.30 (0.25 to 0.34), 0.68 (0.62 to 0.74), and -0.06 (-0.15 to 0.02), and for conventional exercise programmes were 0.99 (0.96 to 1.02), 1.13 (1.09 to 1.17), and 1.27 (1.21 to 1.34) for RA patients, rheumatologists, and physiotherapists, respectively. In all three respondent groups, the outcome expectations of high intensity exercise were significantly less positive than those of conventional exercise programme. CONCLUSIONS: Despite the existing evidence regarding the effectiveness and safety of high intensity exercise programmes, RA patients, rheumatologists, and physiotherapists have more positive expectations of conventional exercise programmes than of high intensity exercise programmes. Physiotherapists were the least positive about outcomes of high intensity exercise programmes while rheumatologists were the most positive. To help the implementation of new insights in the effectiveness of physical therapy modalities in rheumatology, the need for continuous education of patients, rheumatologists and physiotherapists is emphasised.

Arthritis, Rheumatoid↗

PubMed2004

MMP profile in paired serum and synovial fluid samples of patients with rheumatoid arthritis.

OBJECTIVE: To analyse matrix metalloproteinases (MMPs) and tissue inhibitor-1 of MMPs (TIMP-1) levels in the systemic circulation and synovial fluid (SF) of patients with RA and to compare these levels with inflammatory and collagen degradation markers. METHODS: ProMMP-1, -2, -3, -8, -9, TIMP-1, levels of MMP/alpha(2)-macroglobulin complexes, and collagen degradation products were measured by sandwich ELISA, activity assays, and HPLC in paired SF and serum samples from 15 patients with RA and 13 with OA. RESULTS: MMPs were higher in SF of patients with RA than in OA or controls. MMP levels in SF of patients with OA were higher than in controls. In serum, levels of proMMP-3, -8 and -9 were higher in patients with RA than in OA or controls, whereas only proMMP-8 and -9 were higher in serum of patients with OA than in controls. A strong correlation was seen between serum and SF levels of MMP-8 and -9 in RA. Increased levels of MMP/alpha(2)-macroglobulin complexes indicated an MMP/TIMP imbalance in serum and SF in RA. SF hydroxyproline correlated significantly with SF levels of proMMP-9 in RA. CONCLUSIONS: Systemic MMP-8 and -9 levels represent the situation in the inflamed joint; MMP-9 is likely to be involved in degradation of joint collagen. The hypothesis of MMP/TIMP imbalance in RA is strengthened.

Adult↗

PubMed2003

Comparison of the responsiveness of the Harris Hip Score with generic measures for hip function in osteoarthritis of the hip.

OBJECTIVE: To compare responsiveness of the Harris Hip Score with generic measures (that is, the Short Form-36 (SF-36), and a test of walking speed and pain during walking) in patients with osteoarthritis (OA) of the hip. METHOD: The first 75 cases within the population of a randomised clinical trial on manual therapy and exercise therapy were selected for secondary analysis. Experienced (self reported) recovery by the patients after treatment (five weeks) was used as an external criterion for clinically relevant improvement. Responsiveness was evaluated by comparing responsiveness ratios and receiver operating characteristic curves. RESULTS: The responsiveness ratio for the Harris Hip Score was high (1.70) compared with walking speed (0.45), pain during walking (0.66), and the subscales of the SF-36-"bodily pain" (0.42) and "physical functioning" (0.36). The area under the curve also was highest for the Harris Hip Score (0.92) compared with walking speed (0.71), pain during walking (0.73), and the SF-36 subscales-bodily pain and physical functioning (both 0.66). CONCLUSION: The Harris Hip Score is more responsive than the test of walking speed, pain, and subscales for function of the SF-36 in patients with OA of the hip. The Harris Hip Score seems to be a suitable instrument to evaluate change in hip function in patients with OA of the hip.

Aged↗

PubMed2001

Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis.

OBJECTIVE: To investigate the cartilage-degrading capacity of granzyme B and the presence of granzyme B-positive cells at sites of erosion in the rheumatoid synovium. METHODS: Granzyme B was added to [(3)H]proline/[(35)S]sulphate-labelled cartilage matrices and to cartilage explants. Proteoglycan degradation was assessed by the release of (35)S and glycosaminoglycans into the medium and collagen degradation was assessed by the release of (3)H and hydroxyproline and by measuring the fraction of denatured collagen. Granzyme B expression was studied at the invasive front of the synovium by immunohistochemistry. RESULTS: Granzyme B induced loss of both newly synthesized, radiolabelled proteoglycans in cartilage matrices and resident proteoglycans of the cartilage explants. No effect on collagen degradation was found. Granzyme B-positive cells were present throughout the synovium and at the invasive front. CONCLUSION: The presence of granzyme B-positive cells at the invasive front of the synovium together with its ability to degrade articular proteoglycans supports the view that granzyme B may contribute to joint destruction in rheumatoid arthritis.

Animals↗

PubMed2000

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of a cell surface-targeted plasmin inhibitor.

OBJECTIVE: Joint destruction in rheumatoid arthritis (RA) is a result of degradation and invasion of the articular cartilage by the pannus tissue. The present study was undertaken to examine the role of the plasminogen activation system in cartilage degradation and invasion by synovial fibroblasts and investigate a novel gene therapeutic approach using a cell surface-targeted plasmin inhibitor (ATF.BPTI). METHODS: Adenoviral vectors were used for gene transfer. The effects of ATF.BPTI gene transfer on RA synovial fibroblast-dependent cartilage degradation were studied in vitro, and cartilage invasion was studied in vivo in the SCID mouse coimplantation model. RESULTS: The results indicate that cartilage matrix degradation by rheumatoid synovial fibroblasts is plasmin mediated and depends on urokinase-type plasminogen activator for activation. Targeting plasmin inhibition to the cell surface of the fibroblasts by gene transfer of a cell surface-binding plasmin inhibitor resulted in a significant reduction of cartilage matrix degradation in vitro and of cartilage invasion in vivo. Compared with uninfected rheumatoid synovial fibroblasts, the mean +/-SEM cartilage degradation in vitro was reduced to 87.9+/-0.9% after LacZ gene transfer versus a reduction to 24.0+/-1.6% after ATF.BPTI gene transfer (P<0.0001). The mean +/- SEM in vivo cartilage invasion score was 3.1+/-0.4 in the control-transduced fibroblasts and 1.8+/-0.4 in the ATF.BPTI-transduced fibroblasts (P<0.05). CONCLUSION: These results indicate a role of the plasminogen activation system in synovial fibroblast-dependent cartilage degradation and invasion in RA, and demonstrate an effective way to inhibit this by gene transfer of a cell surface-targeted plasmin inhibitor.

Activating Transcription Factors↗

PubMed2000

Urokinase-mediated fibrinolysis in the synovial fluid of rheumatoid arthritis patients may be affected by the inactivation of single chain urokinase type plasminogen activator by thrombin.

BACKGROUND: Excessive fibrin deposition within the inflamed joints of rheumatoid arthritis (RA) patients suggests that local fibrinolysis is inefficient, which seems to be in contrast with the observed increased levels of urokinase type plasminogen activator (u-PA). Thrombin-mediated inactivation of single chain u-PA (scu-PA) into an inactive form called thrombin-cleaved two chain u-PA (tcu-PA/T) may provide a possible explanation for this contradiction. AIM: To assess the occurrence of tcu-PA/T in the synovial fluid of patients with RA and with osteoarthritis (OA), and in the synovial fluid of controls to find support for thrombin-mediated inactivation of scu-PA in RA. METHODS: Levels of scu-PA and tcu-PA/T were measured in the synovial fluid of 20 RA patients, nine OA patients and 14 controls using sensitive bioimmunoassays. Total urokinase antigen was quantified by a urokinase ELISA. RESULTS: tcu-PA/T was found in the synovial fluid of all RA and OA patients. Only in seven of 14 control samples, levels of tcu-PA/T could be measured above the detection limit of the assay (0.2 ng/ml). The concentrations of tcu-PA/T, scu-PA and u-PA:Ag were significantly higher in the synovial fluid of the RA and OA patients as compared with the controls, while the RA patients had significantly higher levels of tcu-PA/T and u-PA:Ag than the OA patients. In RA, tcu-PA/T seemed to account for more than 40% of total urokinase antigen, while the contribution of tcu-PA/T to total urokinase antigen was only minor in OA and the controls (9.0% and 6.6%, respectively). CONCLUSION: A significant part of the high total urokinase antigen in the synovial fluid of RA patients can be attributed to tcu-PA/T, implying that a large amount of scu-PA is not available for fibrinolysis because of its inactivation by thrombin. Thus, thrombin may promote the inflammation process in RA by inhibiting the fibrinolytic system and preventing the removal of fibrin.

Arthritis, Rheumatoid↗

PubMed1999

Fluorogenic MMP activity assay for plasma including MMPs complexed to alpha 2-macroglobulin.

Elevated MMP activities are implicated in tissue degradation in, e.g., arthritis and cancer. The present study was designed to measure MMP enzyme activity in plasma. Free active MMP is unlikely to be present in plasma: upon entering the circulation, active MMP is expected to be captured by the proteinase inhibitor alpha 2-macroglobulin (alpha 2M). Reconstituted MMP-13/alpha 2M complex was unable to degrade collagen (MW 300,000) in contrast to the low-molecular-weight fluorogenic substrate (MW < 1500). Limited access of high-MW substrates to the active site of MMPs captured by alpha 2M presents the most likely explanation. Consistently, the high-MW inhibitor TIMP (MW approximately 28,000) was unable to inhibit MMP/alpha 2M enzyme activity, whereas the low-MW inhibitor BB94 (MW approximately 500) effectively suppressed enzyme activity. By using fluorogenic substrates with Dabcyl/Fluorescein as quencher/fluorophore combin-ation, sensitive MMP-activity assays in plasma were achieved. Spiking of active MMP-13 and MMP-13/alpha 2M complex, and inhibitor studies with TIMP-1 and BB94, indicated that active MMPs are efficiently captured by alpha 2M in plasma. MMP activity was even detected in control plasma, and was significantly increased in plasma from rheumatoid arthritis patients.

Collagen↗

PubMed1998

Amyloidosis mimicking rheumatoid arthritis.

A 49-year-old man presented a clinical picture suggesting seronegative rheumatoid arthritis. He developed severe joint contractions, pasty synovial swelling, macroglossia and proteinurie. Subsequent investigations disclosed light-chain multiple myeloma and A1-amyloid deposits in synovial tissue and skin. A1-amyloidosis should be considered in the differential diagnosis of patients with seronegative polyarthritis. Clues to the diagnosis of amyloid arthropathy are a carpal tunnel syndrome, early occurrence of joint contractures in combination with a relatively mild synovitis and a low ESR as well as the presence of other possible organ involvement with amyloidosis.

Amyloidosis↗

PubMed1998

Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis.

The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radiological joint damage in rat adjuvant arthritis (AA) and on urinary collagen cross-link excretion in patients with RA. In the animal study, adjuvant arthritis was induced in male Lewis rats. From day 7 onward, high-dose TEA (500 mg/kg body weight, once daily) or placebo was administered orally. Study groups consisted of TEA-treated normal rats (C + TEA), placebo-treated normal rats (C + plac), AA rats treated with TEA (AA + TEA) or with placebo (AA + plac). To monitor joint destruction, urinary collagen cross-link excretion (pyridinoline, HP; deoxypyridinoline, LP) was measured by high-performance liquid chromatography at days 14 and 21. Radiological evaluation of joints was performed at day 21. In the patient study, TEA was administered to nine patients with RA as adjuvant medication (approximately 20 mg/kg body weight, three times daily) for 12 weeks. Urinary HP and LP excretion levels were measured before and during TEA treatment, and 4 weeks after the cessation of TEA treatment. In AA + TEA rats, a significant reduction of HP and a tendency towards a reduction of LP excretion were found compared with AA + plac rats (P < 0.05), at day 14, whereas the HP/LP ratio did not change. No difference was observed in HP, LP excretion, HP/LP ratio and radiological damage score between the TEA- and placebo-treated AA rats at day 21. In RA patients, a significant reduction of HP and LP excretion was found during the TEA treatment period (P < 0.05). After the cessation of TEA treatment, HP and LP excretion increased towards baseline levels. No effect on disease activity was observed. The plasmin antagonist TEA reduced the excretion of collagen pyridinoline cross-links in both experimental and rheumatoid arthritis. As such, this study not only supports the involvement of the plasminogen activation system in the destructive phase of arthritis, but also suggests a beneficial effect of therapeutic strategies directed against inhibition of matrix proteolysis.

Amino Acids↗

PubMed1997

Highly increased levels of active stromelysin in rheumatoid synovial fluid determined by a selective fluorogenic assay.

Stromelysin-1 (MMP-3) is an important member of the matrix metalloproteinase family. In joint-degrading diseases like arthritis, elevated levels of MMP-3 protein are detected in synovial fluid using immunological methods. However, these methods do not discriminate between active and inactive enzyme. In the present study, a specific stromelysin activity assay was developed using the selective fluorogenic substrate TNO003 (Dabcyl-Gaba-Arg-Pro-Lys-Pro-Val-Glu / Nva-Trp-Arg-Glu-(EDANS)-Ala-Lys-NH2, / =cleavage site). For its use in biological media, cleavage of TNO003 by enzymes other than stromelysin was effectively blocked by a proteinase inhibitor cocktail. Spiking of MMP-3 to synovial fluid resulted in an MMP-3 concentration-dependent linear increase in activity. The measured MMP-3 activity was not affected by the addition of MMP-13, even in a 5-fold excess over MMP-3. Synovial fluid from rheumatoid arthritis patients demonstrated 100-fold higher levels of active stromelysin than control synovial fluids.

Arthritis, Rheumatoid↗

PubMed1997

Modified proenzymes as artificial substrates for proteolytic enzymes: colorimetric assay of bacterial collagenase and matrix metalloproteinase activity using modified pro-urokinase.

We describe a new principle for assessment of the activity of proteolytic enzymes of all classes and show the application of this principle for the quantitative assay of bacterial collagenase and human matrix metalloproteinases (MMPs). Central to this new principle is the presence of a proenzyme that can be activated into an active enzyme by a single proteolytic event. The regular activation sequence in the proenzyme is replaced using protein engineering by an artificial sequence recognized by the proteinase to be determined. The latter can act as an activator for the newly engineered proenzyme. In the present paper a simple colorimetric assay for the determination for MMPs is described based on this principle. With the aid of protein engineering, a modified pro-urokinase has been prepared in which the activation sequence normally recognized by plasmin (Pro-Arg-Phe-Lys upward arrowIle-Ile-Gly-Gly) has been replaced by a sequence expected to be recognized and hydrolysed by many MMPs (Arg-Pro-Leu-Gly upward arrowIle-Ile-Gly-Gly). The active urokinase resulting from activation of the modified pro-urokinase by a MMP could be measured either directly, using a specific chromogenic peptide substrate for urokinase, or indirectly via urokinase-catalysed plasminogen activation. The response of the assay to equal molar quantities of active MMPs decreases in the order MMP-2>MMP-9>MMP-1>MMP-3>MMP-7. The detection limit for MMP-9 was below 15 pM, corresponding to 3. 75x10(-15) mol per assay. Using the assay, increased MMP activity was detected in synovial tissue extracts from rheumatoid arthritis patients compared with those from osteoarthritis patients, and in stomach tumour extracts as compared with normal stomach tissue extracts.

Arthritis, Rheumatoid↗

PubMed1997

Rheumatic manifestations of hepatitis C virus infection.

Infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis and has been associated with the occurrence of mixed cryoglobulinaemia. Treatment with interferon alpha can lower the titres of HCV, improve liver lesions and decrease cryoglobulins. In this report, a patient with HCV infection is described who developed arthritis, cutaneous vasculitis and sialoadenitis, together with hepatitis and cryoglobulinaemia. Clinical remission, particularly of the systemic symptoms, was achieved during treatment with interferon alpha.

Aged↗

PubMed1997

An enzyme immunoassay for polymorphonuclear leucocyte-mediated fibrinogenolysis.

Upon stimulation, polymorphonuclear leucocytes (PMNs) release potent serine proteases, i.e. elastase, cathepsin G and proteinase 3, which contribute to the degradation of tissue and plasma components. Here, we describe the development of a plasma test to assess PMN-mediated fibrinogenolysis as a biochemical marker for actual PMN-derived proteolysis in vivo, useful for monitoring therapeutic efficacy, i.e. of elastase inhibitors. We generated a monoclonal antibody (MAb), designated 1-1/B3, with a high affinity for elastase-degraded fibrinogen (EDF). The epitope for 1-1/B3 becomes exposed in a time-dependent manner during digestion of fibrinogen with purified PMN-derived serine proteases and with isolated PMNs in vitro. However, 1-1/B3 does not react with plasma fibrinogen or with fibrin(ogen) degradation products generated by plasmin or by other active proteases that may occur locally, i.e. metalloproteases and lysosomal cathepsins. On the basis of MAb 1-1/B3, we developed a plasma test for the assessment of PMN-mediated fibrin(ogen) degradation products (PMN-FDP). In a panel of control plasmas, we observed concentrations of PMN-FDP of 8.2 +/- 0.9 ng mL-1 (n = 18). These values were increased twofold in patients with alpha 1-proteinase inhibitor deficiency (18.6 +/- 3.3 ng mL-1; n = 12; P < 0.0001) and even more in patients with sepsis (365.7 +/- 97.7 ng mL-1; n = 16; P < 0.0001). Furthermore, synovial tissue extracts from patients with rheumatoid arthritis contained increased levels of PMN-FDP, compared with synovial tissue extracts (P < 0.005) from patients with osteoarthritis.

Antibodies, Monoclonal↗

PubMed1997

Bone matrix degradation by the plasminogen activation system. Possible mechanism of bone destruction in arthritis.

The observed increase in urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR) in synovial tissue of patients with rheumatoid arthritis (RA) suggests pathophysiological involvement of the plasminogen activation (PA) system in inflammatory joint disease. In the present study, we investigated the capacity of the PA system to degrade non-mineralized and mineralized bone-like matrix in vitro as a model for bone destruction. Transfected mouse LB6 cell lines, that expressed either human u-PA or u-PAR, were cultured separately and simultaneously on radiolabelled bone matrix in the presence of plasminogen. Osteoblast-like murine calvarial MC3T3-E1 cells were used to produce a well-characterized, highly organized bone-like matrix, that could be mineralized in the presence of beta-glycerol phosphate. Bone matrix degradation was followed by the release of radioactivity in the culture medium. u-PA-producing cells, in contrast to u-PAR-producing cells, degraded both non-mineralized and mineralized bone matrix. This effect could be inhibited by anti-u-PA antibodies, as well as by tranexamic acid and by aprotinin, indicating that the degrading activity is u-PA mediated and plasmin dependent. Co-cultivation of a small portion of u-PA-producing cells with u-PAR-expressing cells resulted in a marked increase in degradation activity. Reduction of this potentiating effect by suramin or the amino-terminal fragment of u-PA, both competitive inhibitors of u-PA receptor binding, shows that this synergistic effect is due to binding of u-PA to u-PAR. u-PAR must be cell associated, as binding of u-PA to a soluble u-PAR prevented this enhancement. The capability of the PA system to degrade bone matrix in vitro, and the previously demonstrated increased expression of u-PA and u-PAR in synovial tissue of patients with RA, further support a role for the PA system in the development of bone erosions.

3T3 Cells↗