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ID PMID Title PublicationDate abstract
17006705 Immunogenicity, efficacy and adverse events of adalimumab in RA patients. 2007 Jan To assess the immunogenicity of adalimumab, a human anti-TNF-alpha mAb, we evaluated the formation of antibodies to adalimumab, efficacy and adverse events among 15 patients with highly active rheumatoid arthritis. Four patients were treated with adalimumab as monotherapy, and 11 patients with concomitant DMARDs. Disease activity was measured by DAS28. The antibodies were detected by ELISA. Thirteen (87%) patients withdrew from therapy within 45 weeks and overall 13 (87%) patients showed antibodies to adalimumab including 11 patients who withdrew from therapy. In four patients without concomitant DMARDs and in nine patients with concomitant DMARDs, we detected anti-adalimumab antibodies. Overall, five of seven patients with adverse drug reactions and all nine patients with lack of efficacy were associated with the formation of antibodies. Two antibody-positive patients developed an exantheme. The results indicate that adalimumab is, in spite of its fully human sequences, immunogenic and induces antibodies in a high rate of adalimumab-treated patients.
15868334 [Current insights into the development of new glucocorticoid receptor ligands]. 2005 Apr Recent insights into the mechanisms of genomic and non-genomic glucocorticoid actions have stimulated the search for novel glucocorticoid receptor ligands. These efforts are driven by the need to improve the benefit-risk ratio of these important drugs. Glucocorticoids are very frequently and successfully used drugs which mediate important immunosuppressive and anti-inflammatory effects, but unfortunately they have pleiotropic effects causing a number of adverse reactions which limit their clinical use, especially at higher dosages and for longer periods. For this reason, novel glucocorticoid receptor ligands are being developed, among them selective glucocorticoid receptor agonists (SEGRAs). SEGRAs are drugs that predominantly induce transrepression effects (inhibition of protein synthesis), whereas the transactivation activity (induction of protein synthesis) is significantly reduced as compared with conventional glucocorticoid drugs. This makes sense since it became evident over the last few years that many adverse effects are predominantly caused by the transactivation mechanism, whereas anti-inflammatory effects are mostly mediated by transrepression mechanisms. Other interesting examples for exciting new developments are NO-glucocorticoids and long-circulating liposomal glucocorticoids. It is, however, true of all these developments that further in vivo and in vitro investigations and clinical trials will have to define in more detail their safety-efficacy profile in order to answer the questions whether these drugs as "improved glucocorticoids" will enter clinical medicine in the near future.
15987596 The expanded endonasal approach: a fully endoscopic transnasal approach and resection of t 2005 Jul The transoral approach to the odontoid process is considered the "gold standard" for resection of extradural lesions at this location. A completely transnasal endoscopic approach is feasible based on anatomic studies and our experience with the expanded endonasal approach for neoplasms of the cranial base. An illustrative case is presented to demonstrate the technical details of a fully transnasal completely endoscopic approach for the resection of the odontoid process. A 73-year-old woman with a long-standing history of rheumatoid arthritis presented with progressive cervicomedullary compression. Complete resection of the odontoid was achieved with no significant morbidity. This is the first reported case of a completely endoscopic resection of the odontoid using a fully transnasal route. The report demonstrates the feasibility of this approach and larger clinical series with long-term follow-up will be needed to determine the reproducibility and validation of any potential benefits.
15934114 Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial 2005 Jun OBJECTIVE: Cortisol, the biologically active glucocorticoid, is a major endogenous antiinflammatory factor in rheumatoid arthritis (RA). The aim of this study was to examine the local conversion of cortisol to biologically inactive cortisone and vice versa (the cortisol-cortisone shuttle) in RA and osteoarthritis (OA) patients. METHODS: Thin-layer chromatography and phosphorimaging were used to examine the cortisol-cortisone shuttle in mixed synovial cells. Double immunohistochemistry was used to assess the key enzymes 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) and 11beta-HSD2 and their possible cellular locations. RESULTS: Double immunohistochemistry demonstrated 11beta-HSD1/2+ macrophages in the sublining area. The ratio of 11beta-HSD2+ cells to 11beta-HSD1+ cells was significantly higher in RA than in OA patients. Cortisol was converted to inactive cortisone in mixed synovial cells from RA and OA patients, which was largely inhibited by carbenoxolone (11beta-HSD1 and 11beta-HSD2 inhibitor). Using metyrapone to inhibit the 11beta-HSD1 reducing reaction (cortisone --> cortisol), we demonstrated that the capacity for reactivation of cortisone to cortisol was significantly higher in OA than in RA patients. Although the capacity for the cortisone-cortisol shuttle was higher in synovial cells from less-inflamed OA tissue compared with inflamed RA tissue, it was obvious that synovial inflammation in RA, but not OA, was related positively to the reactivation of cortisone. This indicates that in RA, a cause other than typical inflammatory factors inhibits the reactivation of cortisone. Since isoproterenol and adenosine inhibited the cortisol-cortisone shuttle, the loss of sympathetic nerve fibers (loss of beta-adrenergic agonist and adenosine) may be the missing link that accounts for the increased cortisol-cortisone shuttle in RA. CONCLUSION: This study demonstrates a reduced capacity for local reactivation of cortisone in RA synovial cells. Since synthetic glucocorticoids also use this reactivation shuttle, the results also apply to therapeutic glucocorticoids. This defective reactivation of cortisone may be an important unrecognized pathophysiologic factor in RA.
15688191 The treatment of osteoporosis in patients with rheumatoid arthritis receiving glucocortico 2005 Nov OBJECTIVE: The purpose of this study was to assess the effects of alendronate and intranasal salmon calcitonin (sCT) treatments on bone mineral density and bone turnover in postmenopausal osteoporotic women with rheumatoid arthritis (RA) receiving low-dose glucocorticoids. METHODS: Fifty osteoporotic postmenopausal women with RA, who had been treated with low-dose corticosteroids for at least 6 months, were randomized to receive alendronate 10 mg/day or sCT 200 IU/day for a period of 24 months. All patients received calcium supplementation 1,000 mg and vitamin D 400 IU daily. Bone mineral density (BMD) of the lumbar spine, femoral neck, and trochanter was measured annually using dual-energy X-ray absorptiometry. Bone metabolism measurements included urinary deoxypyridinoline (DPD), serum bone alkaline phosphatase (BAP), and serum osteocalcin (OC). RESULTS: Over 2 years, the lumbar spine (4.34%, P < 0.001), femoral neck (2.52%, P < 0.05), and trochanteric (1.29%, P < 0.05) BMD in the alendronate group increased significantly. The sCT treatment increased lumbar spine BMD (1.75%, P < 0.05), whereas a significant bone loss occurred at the femoral neck at month 24 (-3.76%, P < 0.01). A nonsignificant decrease in the trochanteric region was observed in the sCT group (-0.81%). The difference between the groups with respect to the femoral neck and trochanteric BMD was statistically significant ( P < 0.001 and P < 0.05, respectively). The decreases in urinary DPD (-21.87%, P < 0.001), serum BAP (-10.60%, P < 0.01), and OC (-19.59%, P < 0.05) values were statistically significant in the alendronate group, whereas nonsignificant decreases were observed in the sCT group (-5.77%, -1.96%, and -4.31%, respectively). A significant difference was found in the DPD and BAP levels between the two treatment groups in favor of the alendronate group at all time points ( P = 0.001 and P < 0.05, respectively). CONCLUSION: The results of this study demonstrated that alendronate treatment produced significantly greater increases in the femoral neck BMD and greater decreases in bone turnover than intranasal sCT in RA patients receiving low dose glucocorticoids.
16870801 Current clinical applications of omega-6 and omega-3 fatty acids. 2006 Aug BACKGROUND: Recent years have brought a resurgence of research interest in fatty acids, with studied fields running the gamut of human disease. This movement has run in parallel with an increased interest in using nutrition modalities as therapeutic measures, as opposed to their conventional role as energy sources. The aim of this manuscript is to provide a basic review of current clinical applications of omega-6 and omega-3 fatty acids, with a particular focus on the latter. METHODS: A selective review of the voluminous literature, including randomized controlled trials, meta-analyses, population studies, and case reports, was used to compile data and identify trends in pertinent clinical applications of fatty acid therapy. CONCLUSIONS: There are a myriad of disorders and maladies that seem to benefit from fatty acid supplementation, specifically omega-3 fatty acids. It has clearly been shown that omega-3 fatty acid supplementation provides a protective benefit in heart disease, and in particular sudden cardiac death. Rheumatoid arthritis (RA) is another disease entity that has been proven to benefit from this nutrition intervention, with improvement in symptoms and diminished nonsteroidal antiinflammatory drug (NSAID) usage. In addition, many psychiatric disorders, particularly schizophrenia and major depressive disorder (MDD), have shown positive results when supplementation has been used as an adjunct to standard pharmacotherapy. The remainder of clinical applications for omega-3 fatty acids requires further investigation. Specifically, according to preliminary clinical evidence, parenteral administration of fatty acids warrants further study.
16084773 FcgammaRIIa is a target for modulation by TNFalpha in human neutrophils. 2005 Oct Activation of neutrophils by the interaction of immune complexes with Fc gamma receptors (FcgammaR) is amplified in tumor necrosis factor-alpha (TNFalpha)-primed cells, whereas interleukin-10 (IL-10) has been reported to suppress cytokine-mediated neutrophil activation. We examined whether the expression and function of FcgammaR in human neutrophils is modulated by TNFalpha and IL-10 in vitro, and whether FcgammaRIIa expression is altered following treatment with the TNFalpha inhibitor infliximab in rheumatoid arthritis (RA) patients in vivo. TNFalpha treatment induced upregulation of expression and function of the major activating Fc receptor, FcgammaRIIa, in neutrophils from healthy donors. Unexpectedly, treatment with IL-10 led to gain of FcgammaRIIa function in TNFalpha-primed neutrophils. In neutrophils from RA patients initiating infliximab therapy and followed longitudinally through consecutive treatments, FcgammaRIIa protein decreased during the course of TNFalpha blockade, indicating that FcgammaRIIa is a target of TNFalpha modulation in human neutrophils in vivo.
15940552 Have traditional DMARDs had their day? Effectiveness of parenteral gold compared to biolog 2005 Jun This review tries to answer the question of whether in the face of the recently introduced biologics conventional disease-modifying antirheumatic drugs (DMARDs) can still be recommended in the treatment of rheumatoid arthritis (RA). We start with an overview of the oldest conventional DMARD, injectable gold (Au), which was introduced in the treatment of RA in the 1920s. The effect of gold is directed at a number of different sites of the immune system. A significant improvement of clinical and biochemical disease activity parameters as well as an inhibition of X-ray progression has been shown in many studies. Head-to-head comparisons between gold and high-dose methotrexate (MTX) demonstrated no significant difference but some advantages for gold. Since trials comparing biologics with gold will never be performed, an indirect comparison was done by analyzing the results of trials with gold with those with biologics. Conclusions from such comparisons have to be drawn with caution especially since the methodology for performing trials has changed with time. We selected four trials with gold (two open, one placebo-controlled, and one comparison with MTX) and five trials with biologics (three placebo-controlled, one dose escalation study, and one comparison with MTX). In all these trials baseline data regarding swollen joint count (SJC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were roughly comparable and, with the exception of interleukin (IL)-1 RA, demonstrated a similar improvement of over 50% already after 6 months [with faster onset with tumor necrosis factor (TNF)-alpha blockade]. American College of Rheumatology (ACR) response data were not available for the older gold trials. European League Against Rheumatism (EULAR) response criteria could be calculated for the Au/MTX trial and were-for these compounds-only slightly inferior to the results with adalimumab. X-ray response is especially difficult to compare across studies. Although an inhibition with Au and MTX could be demonstrated, this occurred-similar to corticosteroid treatment-earlier and more pronounced with TNF-alpha blockers. We confirm the statement of Weinblatt that the most modern DMARDs do not appear to be much better than the oldest one indicating that conventional DMARDs are not outdated. Therefore, a sufficient trial of conventional DMARDs should precede the introduction of treatment with the very expensive biologics.
15658122 Impact of interlaminar graft materials on the fusion status in atlantoaxial transarticular 2005 Jan OBJECT: Structural interlaminar graft materials were used for atlantoaxial transarticular screw fixation (TSF), and its impact on the fusion status was investigated. METHODS: Forty-two patients (10 men, 32 women, mean age 51 years, mean follow-up period 45 months; 30 with rheumatoid arthritis, and 12 with os odontoideum) underwent TSF and modified Brooks posterior wiring involving titanium cables. As interlaminar graft materials, autologous bone from posterior iliac crest alone was used in 20 patients (Group A), and a structural spacer (13 ceramic spacers, nine titanium mesh cages) in 22 (Group B). Lateral radiographs were evaluated to determine bone fusion, alignment of the cervical spine, and wire loosening. Solid osseous fusion was obtained in 95% of Group A and 96% of Group B patients. The mean atlantoaxial angle was 19.1+/-9.7 degrees and 16.7+/-10.4 degrees before surgery (p = 0.45), and 27.4+/-7.8 degrees and 22.1+/-5.5 degrees after surgery (p = 0.02) in Groups A and B, respectively. Atlantoaxial hyperlordosis (atlantoaxial angle > or = 30 degrees) was observed in 32% of Group A and 18% of Group B patients (p = 0.26). Postoperative kyphosis occurred in 40% of Group A and 23% of Group B patients (p = 0.28). Loosening of the cable was demonstrated in 50% of Group A and 36% of Group B patients(p = 0.37). In Group B patients maintenance of cervical lordosis was more likely than in those in Group A, although the differences did not reach statistical significance. CONCLUSIONS: These results indicate that structural interlaminar spacers can maintain proper cervical alignment without a decease in the fusion rate; the authors recommend their use in conjunction with TSF.
16164221 [RANKL/RANK signaling-inhibitor]. 2005 Sep Osteoclast differentiation requires the interaction of RANK (receptor activator of NF kappaB) and RANK ligand, conserved member of the TNF (tumor necrosis factor) receptor and TNF families, respectively. We tested the ability of a peptide mimic (WP9QY) of a critical contact site on the TNF receptor to inhibit RANK ligand induced osteoclastogenesis and discuss whether it could work as both TNF-alpha and RANKL antagonists, and the possibility of the drug development using the techniques in the structural biology.
16508937 Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti-citrullinated protein 2006 Mar OBJECTIVE: To test the hypothesis that deimination of viral sequences containing Arg-Gly repeats could generate epitopes recognized by anti-citrullinated protein antibodies (ACPAs) that are present in rheumatoid arthritis (RA) sera. METHODS: Multiple antigen peptides derived from Epstein-Barr virus (EBV)-encoded Epstein-Barr nuclear antigen 1 (EBNA-1) were synthesized, substituting the arginines with citrulline, and were used to screen RA sera. Anti-cyclic citrullinated peptide antibodies were purified by affinity chromatography and tested on a panel of in vitro deiminated proteins. Their ability to bind in vivo deiminated proteins was evaluated by immunoprecipitation, using EBV-infected cell lines. RESULTS: Antibodies specific for a peptide corresponding to the EBNA-1(35-58) sequence containing citrulline in place of arginine (viral citrullinated peptide [VCP]) were detected in 50% of RA sera and in <5% of normal and disease control sera. In addition, affinity-purified anti-VCP antibodies from RA sera reacted with filaggrin-derived citrullinated peptides, with deiminated fibrinogen, and with deiminated recombinant EBNA-1. Moreover, anti-VCP antibodies immunoprecipitated, from the lysate of calcium ionophore-stimulated lymphoblastoid cell lines, an 80-kd band that was reactive with a monoclonal anti-EBNA-1 antibody and with anti-modified citrulline antibodies. CONCLUSION: These data indicate that ACPAs react with a viral deiminated protein and suggest that EBV infection may play a role in the induction of these RA-specific antibodies.
16906370 Acceptability and usefulness of mizoribine in the management of rheumatoid arthritis in me 2006 This report documents the results of a study performed to examine clinical use of mizoribine (MZR), using data from a large-scale prospective cohort study, IORRA (Institute of Rheumatology Rheumatoid Arthritis). The number of patients with RA entered in this study from October 2000 through October 2003 was 6238. Three hundred and six patients (4.9%) received MZR therapy. Mizoribine users who were taking methotrexate (MTX) (MTX-MZR group, n = 94) and over 70 years of age (elderly group, n = 45) were collected. Cumulative retention rates of MZR were calculated by Kaplan-Meier analysis. Median drug survival of MZR was 28 months for the poor responders to MTX and 43 months for the poor responders to MZR, with no significant difference between these groups. Cumulative retention rate of MZR in the elderly group did not show a significant difference compared to that in patients aged under 70 years. Ten patients (10.6%) in the MTX-MZR group and 10 patients (22.2%) in the elderly group experienced adverse effects of MZR. None of these adverse effects was serious. This study indicated that, although MZR has not been frequently prescribed for RA patients, it may be useful and relatively safe for patients who are poor responders to MTX as an additional regimen to MTX therapy as well as for elderly patients.
15999628 [The medical reason for the prescription of COX-2 selective cyclo oxygenase inhibitor rofe 2005 May This study was designed to analyze reasons why rheumatologists prescribed coxibs instead of non-selective NSAIDs in the treatment of rheumatoid arthritis in Austria. A simple questionnaire was distributed among interested doctors of internal or orthopedic medicine in medical practices treating patients with rheumatic diseases. 730 patients with rheumatoid arthritis could be included in this study. The argument most often mentioned was the low incidence of gastrointestinal side-effects followed by analgesic effectiveness compared with non-selective NSAIDs. Easy to use, age of patients and general tolerability were further reasons for the decision to prescribe rofecoxib.
17080518 An index of patient reported outcomes (PRO-Index) discriminates effectively between active 2006 Nov OBJECTIVE: To analyze 2 indices composed of the 3 patient reported outcomes (PRO) in the American College of Rheumatology (ACR) Core Data Set--physical function, pain, and global estimate--without joint count or laboratory data, for capacities to distinguish active from control treatments in 4 pivotal clinical trials. METHODS: Data from 4 clinical trials involving adalimumab, in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARD) or as monotherapy, versus control treatment were made available to analyze properties of various indices. A categorical PRO-Index M was defined as "majority" improvement in 2 of the 3 PRO measures at 20%, 50%, and 70% levels; results were evaluated to analyze agreement with ACR20, ACR50, ACR70 responses and an "all Core Data Set measures" index based on 4 of the 7 measures having such levels of improvement. A continuous PRO-Index C was defined as the median or 2nd highest of 3 percentage differences from baseline to endpoint; results were evaluated to analyze agreement with a continuous ACR-N, "all Core Data Set measures" index, and Disease Activity Score 28 (DAS28). RESULTS: All indices distinguished active versus control treatment at similar levels, including PRO-Index M versus ACR20, ACR50, and ACR70 responses, and PRO-Index C versus DAS28. CONCLUSION: PRO indices based only on patient questionnaire data, without joint counts or laboratory tests, may be useful quantitative measures of therapeutic efficacy for use in standard rheumatology clinical care.
16126970 Investigation of arthritic joint destruction by a novel fibroblast-based model. 2005 Jun The key pathologic mechanism in rheumatoid arthritis (RA) is the destruction of cartilage by fibroblasts. In a severe combined immunodeficient (SCID) mouse model, this process can be modulated by gene transfer using invasive LS48 fibroblasts. This study aims to investigate the effect of interleukins (IL) -11 and -12 on cartilage destruction when transferred into LS48, and of IL-15 when transfected into non-invasive 3T3 cells; to compare three transduction systems (a lentiviral vector system, a retroviral vector system, and a particle-mediated gene transfer); and to establish an in vitro cartilage destruction system based on LS48 cells. Transduced fibroblasts were injected into SCID mice knee joints, and disease progression assessed microscopically. Distinctive morphologic pattern revealed invasion of fibroblasts into the articular cartilage by transfected, as well as non-transfected, LS48 cells. IL-12 and IL-15 did not alter swelling or cartilage destruction. Animals treated with IL-11-transfected cells showed reduced cartilage damage but no changes in swelling. Efficacy of gene transfer to establish transfected fibroblasts was shown to be >85% for lentiviral transfer, compared to <10% for retroviral transfer and gene gun. Furthermore, cells were co-incubated with porcine cartilage. Transduction of IL-11 led to a reduction of apoptosis in chondrocytes. These findings suggest that cartilage destruction by invasive fibroblasts can be modulated by gene transfer. Lentiviral vector systems offer the most effective approach for gene transduction. In vitro fibroblast/cartilage co-cultures present a convenient system for the assessment of novel therapeutic strategies toward reduction of articular destruction.
16200609 Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease 2005 Oct OBJECTIVE: To compare the prevalence and severity of coronary-artery atherosclerosis in patients with early and established rheumatoid arthritis (RA) and controls. METHODS: Electron-beam computed tomography was used to measure the extent of coronary-artery calcification in 227 subjects, of whom 70 had early RA, 71 had established RA, and 86 were controls. Coronary-artery calcification calculated according to the Agatston calcium score was compared in patients and controls, and its relationship to clinical characteristics was examined. Adjusted odds ratios (ORs) were obtained with the use of proportional odds logistic regression models to determine independent associations of early and established RA and coronary-artery calcification. RESULTS: Calcium scores were higher in patients with established RA (median 40.2, interquartile range [IQR] 0-358.8) compared with those with early disease (median 0, IQR 0-42.6) and controls (median 0, IQR 0-19.2) (P = 0.001). Coronary-artery calcification occurred more frequently in patients with established RA (60.6%) than in patients with early RA (42.9%) and control subjects (38.4%) (P = 0.016) The OR for the likelihood of having more severe coronary-artery calcification (defined as an Agatston score >109) in patients with established disease was 3.42 (P = 0.002) after adjusting for cardiovascular risk factors. Among patients with RA, smoking (OR 1.02, P = 0.04) and an elevated erythrocyte sedimentation rate (OR 1.02, P = 0.05) were associated with more severe coronary-artery calcification after adjustment for age and sex. CONCLUSION: The prevalence and severity of coronary calcification is increased in patients with established RA and is related, in part, to smoking and an increased erythrocyte sedimentation rate.
15686237 Total elbow arthroplasty after previous resection of the radial head and synovectomy. 2005 Jan We examined the effects of previous resection of the radial head and synovectomy on the outcome of subsequent total elbow arthroplasty in patients with rheumatoid arthritis. Fifteen elbows with a history of resection and synovectomy were compared with a control group of patients who had elbow arthroplasty with an implant of the same design. The mean age in both groups was 63 years. In the study group, resection of the radial head and synovectomy had been undertaken at a mean of 8.9 years before arthroplasty. The mean radiological follow-up for the 13 available patients in the study group was 5.89 years (0.3 to 11.0) and in the control group was 6.6 years (2.2 to 12.6). There were no revisions in either group. The mean Mayo elbow performance score improved from 29 to 96 in the study group, with similar improvement in the control group (28 to 87). The study group had excellent results in 13 elbows and good results in two. The control group had excellent results in seven and good results in six. Our experience indicates that previous resection of the radial head and synovectomy are not associated with an increased rate of revision following subsequent arthroplasty of the elbow. However, there was a higher rate of complication in the study group compared with the control group.
17143598 Correlation between Yersinia enterocolitica and type I collagen reactivity in patients wit 2007 May We investigated the association with Yersinia infection in patients with arthropathies in our region. To assess the reactivity to articular antigens, the correlation of anti-Yersinia with anti-type I and type II collagen antibodies was studied. Sera from 124 patients with musculoskeletal symptoms, and 47 synovial fluids (SF) from patients with rheumatoid arthritis (RA), spondyloarthopathies (SpA) or osteoarthritis (OA) were examined. Immunoglobulins against Yersinia enterocolitica, type I and type II collagens were determined by enzyme-linked immunosorbent assay. Immunoglobulin (Ig) A to Yersinia lipopolysaccharide (LPS) was present in 13/124 sera (10%) and 3/47 SF (6%). By Western blot, IgA to Yersinia outer proteins (Yops) was found in 14/124 sera (11%) and 2/47 SF (4%). Yersinia DNA from SF was not amplified by polymerase chain reaction. We found a significant correlation with anti-collagen type I but not type II antibodies. These results suggest different reactivity to articular collagen in patients with Yersinia antibodies.
15693006 Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan su 2005 Feb OBJECTIVE: EMR2 and CD97 are closely related members of the epidermal growth factor (EGF)-TM7 family of adhesion class 7-span transmembrane (TM7) receptors. Chondroitin sulfates (CS) have recently been identified as ligands for EMR2 and CD97. CS have been implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine the expression of EMR2 and the distribution of EMR2 and CD97 ligands within RA synovial tissue (ST). METHODS: ST samples were obtained by arthroscopy from 19 patients with RA, 13 patients with inflammatory osteoarthritis (OA), and 13 patients with reactive arthritis (ReA). Immunohistochemistry was performed with a monoclonal antibody against EMR2, and stained STs were analyzed by digital image analysis. Coexpression of EMR2 with cell lineage- and activation-specific markers was determined by double immunofluorescence microscopy. To evaluate the expression of EMR2 and CD97 ligands in RA synovium, binding assays were performed using EMR2- and CD97-specific multivalent fluorescent probes. RESULTS: EMR2 expression in the synovial sublining was found to be significantly higher in RA patients compared with OA and ReA control patients. Most EMR2+ cells were macrophages and dendritic cells expressing costimulatory molecules and tumor necrosis factor alpha. Dermatan sulfate was shown to be the ligand of the largest isoforms of EMR2 and CD97 in rheumatoid synovium. In addition, the smaller isoforms of CD97, but not those of EMR2, bound CD55 on fibroblast-like synoviocytes. CONCLUSION: The EGF-TM7 receptors EMR2 and CD97 are abundantly expressed on myeloid cells in ST of RA patients where their cognate ligands dermatan sulfate and CD55 are detected. These results suggest that these interactions may facilitate the retention of activated macrophages in the synovium.
17009259 Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: imp 2006 Oct OBJECTIVE: We have previously reported the up-regulation of matrix metalloproteinase 10 (MMP-10) following treatment with the procatabolic stimulus of interleukin-1 (IL-1) and oncostatin M (OSM) in chondrocytes. Although MMP-10 is closely related to MMP-3, little is known about the role of MMP-10 in cartilage catabolism. The purpose of this study was to determine whether MMP-10 is expressed in connective tissue cells and to assess how it may contribute to cartilage collagenolysis. METHODS: MMP gene expression was assessed by real-time polymerase chain reaction using RNA from human articular chondrocytes and synovial fibroblasts stimulated with IL-1 plus OSM or tumor necrosis factor alpha (TNFalpha) plus OSM. Synovial fluid levels of MMP-10 were determined by specific immunoassay. Recombinant procollagenases were used in activation studies. Immunohistochemistry assessed MMP-10 expression in diseased joint tissues. RESULTS: MMP-10 expression was confirmed in both chondrocytes and synovial fibroblasts following stimulation with either IL-1 plus OSM or TNFalpha plus OSM, and MMP-10 was detected in synovial fluid samples from patients with various arthropathies. Exogenous MMP-10 significantly enhanced collagenolysis from IL-1 plus OSM-stimulated cartilage, and MMP-10 activated proMMP-1, proMMP-8, and proMMP-13. Immunohistochemistry revealed the presence of MMP-10 in the synovium and cartilage of an IL-1 plus OSM-induced model of arthritis as well as in samples of diseased human tissues. CONCLUSION: We confirm that both synovial fibroblasts and articular chondrocytes express MMP-10 following treatment with procatabolic stimuli. Furthermore, the detectable levels of synovial fluid MMP-10 and the histologic detection of this proteinase in diseased joint tissues strongly implicate MMP-10 in the cartilage degradome during arthritis. The ability of MMP-10 to superactivate procollagenases that are relevant to cartilage degradation suggests that this activation represents an important mechanism by which this MMP contributes to tissue destruction in arthritis.