Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
12405893 Remission of lymphoma after drug withdrawal in rheumatoid arthritis. 2002 Nov 4 A 63-year-old man with rheumatoid arthritis presented with pain and swelling of his right buttock. Imaging and tissue biopsy revealed a diffuse large B-cell, non-Hodgkin's lymphoma. The disease-modifying drugs he was taking, cyclosporin and methotrexate, were stopped, and the lymphoma resolved spontaneously without the use of chemotherapy.
15495594 [Anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: relation with clini 2004 Jun The specificity and sensitivity of anti-cyclic citrullinated peptide antibodies (anti-CCP) was examined in Latin-American patients with rheumatoid arthritis (RA). The variables considered included: 1) relation with the activity of disease, 2) extra-articular manifestations (EAM), 3) synthesis of cytokines (IL-4, IL-10, IL-12, TNF-alpha, and IFN-gamma) and IgM and IgA rheumatoid factor (RF), and 4) the association with HLA-DRB1 polymorphism. Seventy-nine RA patients were assessed (69 with established RA, and 10 with recent-onset RA not receiving any treatment), 56 with ankylosing spondylitis (AS), 25 with systemic lupus erythematosus (SLE), 50 with primary Sjögren's syndrome (pSS), and 10 healthy individuals. Of the 69 patients with established RA, 36 were reexamined 2 years later. The activity of the RA was measured by criteria adopted by the American College of Rheumatology. Anti-CCP2, RF and cytokines levels were determined by ELISA. HLA genotypes were established by first, PCR sequence amplification using sequence-specific primers and then, complete sequencing of the product. Anti-CCP antibodies were observed in 96% of patients with RA during the first evaluation and in 86% at the second evaluation (p = 0.12). No significant change in antibody titre was observed between the two evaluations (131 +/- 58.7 and 130.6 +/- 67.1 IU, respectively). The overall sensitivity and specificity was 94% and 92%, respectively; however, at titres > 60 IU, the values were 84% and 95%, respectively. The anti-CCP likelihood ratio positive test was 12 and the likelihood ratio negative test was 0.06. The positive predictive value was 87%, and the negative predictive value was 96%. Anti-CCP antibodies were observed in 12% of SLE and pSS patients, in 2% of AS patients, and in 10% of healthy controls. In RA patients, these antibodies were not associated with the activity of disease, EAM or HLA-DRB1 alleles; no significant correlation was observed between antibody titre and cytokines level. Although anti-CCP antibodies have potential as a diagnostic tool for RA, they are not useful for monitoring clinical activity or predicting the clinical course of disease. Antibody synthesis is HLA-DRB1 independent and not correlated with Th1/Th2 cytokines.
15893949 Do arachidonic acid and its metabolites, secreted by rheumatoid and osteoarthritic synovia 2005 Dec AIMS: To further characterize factors secreted in vitro by osteoarthritic and rheumatoid arthritis synovial membranes that inhibit DNA synthesis by cultured human articular chondrocytes, and extend these findings to synovial fluid. MATERIAL AND METHODS: Synovial tissue, synovial fluid and articular cartilage were obtained at surgery from two patients suffering rheumatoid arthritis and two other patients suffering from osteoarthritis. Synovial tissue was incubated in DMEM, then condition media and synovial fluids were extracted with methanol. Methanol extracts and extracted residues (hyaluronic acid, proteins) were assayed for their capacity to inhibit DNA synthesis in articular chondrocytes. Methanol extracts were also fractionated by thin layer chromatography on silica-coated plates and recovered fractions similarly tested. RESULTS: All extracts exhibited strong and concentration-dependent inhibition of [3H]-thymidine incorporation. The most potent inhibition was obtained with the extracts from rheumatoid joints and the least potent inhibition was with synovial fluids. The removal of active substances with methanol leaves an inactive residue. Methanol extraction does not alter the mitogenic activity of five exogenous growth factors and two cytokines, thus suggesting that such activity is entirely due to lipids. The bulk of anti-mitotic factors extracted by methanol co-migrate when fractionated by thin layer chromatography on silica-coated plates with arachidonic acid and its lipo-oxygenase metabolites. IN CONCLUSION: Inflamed synovium produces and releases lipids, most probably arachidonic acid metabolites that inhibit cell proliferation thus limiting inflammation and pannus formation in arthritis.
12610800 Prevalence of rheumatoid arthritis and hepatitis C in those age 60 and older in a US popul 2003 Mar OBJECTIVE: A positive association between rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection has been reported in clinic based cross sectional studies. We investigated if RA and HCV are associated in a population based survey. METHODS: Using data from the National Health and Nutrition Examination Survey III, hepatitis C and RA status were determined for subjects > or = 60 years of age. RA was defined to be present when 3 of 6 American College of Rheumatology (ACR) criteria were met. RESULTS: Of 6596 subjects, 1827 (27.7%) were excluded due to missing data. Of the remaining 4769, 196 subjects (4.1%) met our modified ACR criteria for probable RA: 63 tested positive for anti-HCV antibodies (1.3%) while 35 were HCV RNA positive (0.7%). Two subjects had both HCV antibodies and RA, while one subject was both HCV RNA positive and had RA. HCV antibody positivity was not associated with RA (OR 0.44, 95% CI 0.07-2.80). Similarly, HCV positivity by polymerase chain reaction was not associated with RA (OR 0.77, 95% CI 0.10-6.19). CONCLUSION: These results argue against a potential role for HCV in the etiology of RA in the US population aged 60 years and over.
15252214 No association between tumour necrosis factor receptor type 2 gene polymorphism and rheuma 2004 Oct OBJECTIVES: To assess the association between the tumour necrosis factor receptor 2 (TNFR2) 196 M/R single-nucleotide polymorphism and rheumatoid arthritis (RA) severity by taking advantage of the extremes of phenotype that exist in arthritis. METHODS: From the Leiden Early Arthritis Cohort (1700 patients), we selected patients who initially had the diagnosis of definite or probable RA according to the ACR criteria and developed complete remission (71 patients) or had the worst progression, to destructive disease (72 patients). A group of 135 healthy controls was included. The TNFR2 genotype was determined in these groups. RESULTS: The extremes of phenotypes did not differ significantly in genotype distribution. No difference in genotype distribution between rheumatoid arthritis patients and healthy controls was observed. CONCLUSION: Our study demonstrates that even by comparing the extremes of phenotypes no association between the TNFR2 genotype and disease severity can be detected in Caucasian patients with sporadic RA.
15039637 Proinflammatory cytokines increase iron uptake into human monocytes and synovial fibroblas 2004 Apr BACKGROUND: It has been hypothesized that iron is stored in the synovium of patients with rheumatoid arthritis which perpetuates inflamation by aiding the production of oxygen free radicals. Proinflammatory cytokines are produced by macrophages and lymphocytes present within synovium and by mononuclear cells of in synovial fluid from patients with rheumatoid arthritis. There are two known systems for iron uptake. The first involves binding of iron to transferrin and uptake via transferrin receptors. The second involves uptake by low molecular weight organic anions such as ascorbate and citrate (non-transferrin bound uptake). MATERIALS/METHODS: Proinflammatory cytokines (IL-1, IL-6, TNFalpha and interferon gamma) were added to fibroblasts isolated from patients with rheumatoid arthritis and human monocytes in culture and their effect on 59Fe-transferrin and citrate uptake was determined. RESULTS: Proinflammatory cytokines increase transferrin and non-transferrin bound iron uptake into human monocytes and increase transferrin-bound iron uptake by synovial fibroblasts, but have no effect on non-transferrin bound uptake into fibroblasts. CONCLUSIONS: Proinflammatory cytokines produced in human rheumatoid arthritis synovium and synovial fluid may contribute to the accumulation of iron that occurs in rheumatoid arthritis synovium which may lead to damage to synovial fibroblasts, macrophages and lymphocytes.
12509625 Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spo 2003 Jan OBJECTIVES: To demonstrate the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in synovial tissue from rheumatoid arthritis (RA) patients, establish the cell lineage expressing OPG and compare the expression of OPG in RA, spondyloarthropathies, osteoarthritis and normal synovial tissue. METHODS: Synovial biopsy specimens were obtained at arthroscopy from 16 RA and 12 spondyloarthropathy patients with active synovitis of a knee joint, six RA patients with no evidence of active synovitis, 10 patients with osteoarthritis and 18 normal subjects. Immunohistological analysis was performed using monoclonal antibodies (mAb) to detect OPG and RANKL expression. In addition, dual immunohistochemical evaluation was performed with lineage-specific monoclonal antibodies (macrophages, fibroblasts and endothelial cells) and OPG to determine the cell lineages expressing OPG. The sections were evaluated by computer-assisted image analysis and semiquantitative analysis. RESULTS: Two patterns of OPG expression were seen, one exclusively in endothelial cells and one expressed predominantly in macrophages in the synovial lining layer. Both patterns of OPG staining could be blocked with excess recombinant OPG. Endothelial and synovial lining expression of OPG was seen in all synovial tissues except those from patients with active RA. In contrast, RANKL expression was seen predominantly in synovial tissue from patients with active disease, mainly in sublining regions, particularly within areas of lymphocyte infiltration. CONCLUSIONS: OPG expression on macrophage type synovial lining cells as well as endothelial cells is deficient in RA patients with active synovitis, in contrast to that seen in spondyloarthropathy patients with active synovitis. This deficiency in OPG expression in the inflamed joint of RA patients may be important in the development of radiologically defined joint erosions.
12110122 Matrix metalloproteinases in arthritic disease. 2002 The role of matrix metalloproteinases in the degradative events invoked in the cartilage and bone of arthritic joints has long been appreciated and attempts at the development of proteinase inhibitors as potential therapeutic agents have been made. However, the spectrum of these enzymes orchestrating connective tissue turnover and general biology is much larger than anticipated. Biochemical studies of the individual members of the matrix metalloproteinase family are now underway, ultimately leading to a more detailed understanding of the function of their domain structures and to defining their specific role in cellular systems and the way that they are regulated. Coupled with a more comprehensive and detailed study of proteinase expression in different cells of joint tissues during the progress of arthritic diseases, it will be possible for the future development and application of highly specific proteinase inhibitors to be directed at specific key cellular events.
15322815 The relationship between arthritis and human parvovirus B19 infection. 2005 Nov In order to evaluate the role of human parvovirus B19 in the etiopathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), synovial fluid and blood specimens were collected at 1-month intervals from 20 patients with early synovitis (ES) and 31 with RA. Blood specimens were also collected from 25 patients with SLE, 25 with osteoarthritis (OA) as the diseased control group, and 50 healthy blood donors (HBD) as the healthy control group. Detection of B19 IgM and B19 IgG were performed by enzyme-linked immunosorbent assay from serum specimens, and B19 DNA was detected by polymerase chain reaction from synovial fluid samples. B19 IgM, B19 IgG, and B19 DNA were found in the three patients of the ES group. Subsequently, two of them were diagnosed with RA and one with SLE. B19 DNA was also detected in the synovial fluid of eight patients in the RA group. Of them, all were positive for B19 IgG and half were positive for B19 IgM. B19 IgM was not detected in either of the control groups. To define the role of B19 in the etiopathogenesis and prognosis of undiagnosed arthritis and other chronic inflammatory diseases such as RA and SLE, we need broader serial and prospective studies based on clinical and laboratory collaboration. In conjunction with case reports, these studies would also serve to detect other possible factors in the etiopathogenesis of chronic inflammatory diseases.
12784383 Identification of self-epitopes recognized by T cells in rheumatoid arthritis demonstrates 2003 Jun OBJECTIVE: To identify novel arthritis-associated and/or cartilage-specific self-epitopes recognized by T cells in patients with rheumatoid arthritis (RA). METHODS: Human analogs of several self-epitopes recognized in the rat adjuvant arthritis (AA) model (n = 13) were tested for T cell recognition in patients with RA and healthy controls. Recognition was assessed by proliferative activity of peripheral blood mononuclear cells (PBMC). In addition, cytokine production was determined. RESULTS: Six out of the 13 peptides recognized during AA were also recognized by more than 20% of the RA patients, in contrast to only one out of the 16 control peptides that were not recognized during AA. The highest proliferative responses were to matrix metalloproteinase (MMP)-derived peptides. The response to a MMP-1 epitope was significantly higher in RA patients than in healthy controls. Moreover, this MMP-1 epitope increased interleukin 4 (IL-4) production of RA PBMC and decreased IL-4 production by control PBMC. The proliferative response to a MMP-3 epitope was similar in RA patients and controls; however, the MMP-3 epitope increased IL-4, and concomitantly IL-1beta and tumor necrosis factor-a production of RA PBMC, whereas these cytokines were unaffected in control PBMC. CONCLUSION: This study shows the presence of immune reactions to MMP-derived T cell epitopes that are associated with RA, suggesting a novel role of MMP in RA.
15459487 Investigation of the prognostic value of TNF-alpha gene polymorphism among patients treate 2004 OBJECTIVES: Infliximab, a chimeric anti-tumor necrosis factor (TNF) antibody, is highly effective for the treatment of Crohn's disease (CD) and rheumatoid arthritis (RA). Our experiments focused on RA and CD patients receiving infliximab. Since cytokine production is largely determined by genetic factors, the promoter polymorphisms of TNF-alpha were examined among these patients. Additionally, the changes caused by infliximab in the TNF-alpha-producing ability and apoptosis of peripheral blood mononuclear cells (PBMCs) were investigated. METHODS: The TNF-alpha genotypes were analyzed by PCR-RFLP. The in vitro TNF-alpha production of the PBMCs was detected by flow cytometric analysis. The TNF-alpha concentration in the supernatant was measured by bioassay. Apoptosis was detected by annexin V-fluorescein isothiocyanate labeling. RESULTS AND CONCLUSIONS: 8 of the 12 nonresponder patients carried the TNF A allele associated with high TNF-alpha production. We suggest that the determination of TNF polymorphism may help identify more suitable candidates for infliximab treatment. Although in vitro infliximab treatment for 48 h resulted in significant (44.2 +/- 1.17%) apoptosis in PBMCs, in ex vivo samples from RA patients who received infliximab, apoptosis was only 13.3 +/- 1.6%. Furthermore, infliximab did not result in irreversible inhibition of the TNF-alpha-producing ability or in the significant apoptosis of PBMCs.
12195320 [Tubulointerstitial nephritis and uveitis (TINU syndrome) - comorbidity and complications 2002 Jul BACKGROUND: TINU syndrome probably is a frequently overlooked disease where uveitis occurs in association with acute tubulointerstitial nephritis. Diagnostic criteria have been published recently. PATIENTS AND METHODS: In this retrospective case series the charts of four consecutive patients with TINU syndrome (follow-up 36, 23, 17, and 12 months, respectively) were analysed, including comorbidity and complications, and the literature was reviewed. RESULTS: Two patients were treated with methotrexate or ciclosporin A and mycophenolate mofetil. In one patient autoimmune thyroiditis was known. During the follow-up, symptoms indicative of rheumatoid arthritis were observed. Because of her uveitis she required methotrexate therapy. Three patients were obese (mean BMI 32.2 kg/m (2)). Ocular complications were posterior synechiae (two patients) and papillary and macular oedema (three patients). One patient developed cerebrospinal hypertension under ciclosporin A treatment which resolved after discontinuation of therapy. CONCLUSIONS: Patients with definite TINU syndrome frequently suffer from other diseases and associated immune phenomena. The course of the disease can vary considerably. Complications do occur, despite overall good prognosis. Regional and systemic steroids may be sufficient; frequently steroid sparing immunosuppressives are necessary at least temporarily. Patients with this multiorgan disease do need to be followed by a paediatrician or a medical specialist.
12029585 [Review and comparison of culture-techniques for articular chondrocytes]. 2002 Mar AIM: In-vitro techniques for articular chondrocytes allow the analysis of their metabolism in the presence and absence of mediators or drugs against osteoarthritis or rheumatoid arthritis, as well as the synthesis of de-novo cartilage tissue for implantation into articular defects in vivo. This review aims to give an overview about the basics of different methods of cultivation of articular chondrocytes and about several specific demands (e.g., phenotypical stability with synthesis of aggrecan and type-II collagen, no cell-to-cell contact, low proliferation rates, low matrix molecule turn-over) to such methods. METHOD: Current techniques for the cultivation of articular chondrocytes and their development were identified via "medline". Their evaluation was based on our own experience and on data from the literature. RESULTS: Two- and three-dimensional culture systems are employed to maintain articular chondrocytes in vitro. Two-dimensional cultures (monolayer) support the proliferation of articular chondrocytes, but lead to a de-differentiation to fibroblast-like cells. Three-dimensional set-ups (e.g., organ, alginate, agarose cultures) not only maintain the articular cartilage phenotype, but they also support the re-differentiation of de-differentiated chondrocytes. CONCLUSION: The choice of a culture system for in-vitro studies with articular chondrocytes should be adapted to the question asked.
12077221 Cutting edge: molecular portrait of human autoimmune disease. 2002 Jul 1 Autoimmune diseases affect 3-5% of the population, are mediated by the immune response to self-Ags, and are characterized by the site of tissue destruction. We compared expression levels of >4,000 genes in PBMC of control individuals before and after immunization to those of individuals with four distinct autoimmune diseases. The gene expression profile of the normal immune response exhibits coordinate changes in expression of genes with related functions over time. In contrast, each individual from all autoimmune diseases displays a similar gene expression profile unrelated to the pattern of the immunized group. To our surprise, genes with a distinct expression pattern in autoimmunity are not necessarily "immune response" genes, but are genes that encode proteins involved in apoptosis, cell cycle progression, cell differentiation, and cell migration.
14751100 Radiographic evaluation of osseointegration and loosening of titanium implants in the MCP 2004 Jan PURPOSE: Good to excellent clinical results have been shown in the initial studies on osseointegrated metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint implants that consist of a flexible silicone spacer connected to osseointegrated titanium fixtures. A high fracture rate of the silicone spacer, however, has been reported, diminishing the value of this implant system. The purpose of this study was to evaluate the osseointegration of the titanium fixture itself in a large study group and compare patients with rheumatoid arthritis with those with osteoarthrosis as a base for further development of the implant concept. METHODS: Two hundred thirty-nine implants (27 PIP, 212 MCP) in 86 patients were retrospectively evaluated radiographically. Two hundred implants were in patients with rheumatoid arthritis. Radiographic evaluation included measuring the length and width of resorption zones around the titanium fixtures. A scoring system was used that grouped observations in 4 groups, from 0 (little or no change) to 3 (loosening). Status of the silicone spacer was also noted. RESULTS: At follow-up evaluation an average of 41 months (range, 12-103 months) after surgery, complete osseointegration was found in 450 of 478 fixtures (94%). Loosening was found in 10 proximal and 18 distal fixtures. The proximal fixtures showed loosening mainly during the first 3 years after surgery and the distal fixtures also had loosening. In the 31 MCP joint implants that were evaluated for more than 5 years, the osseointegration rate was 97%. CONCLUSIONS: Implant stem fixation with osseointegrated titanium fixtures is a valuable method that works well in rheumatoid arthritis patients. Further development will focus on a more durable constrained joint mechanism.
15016749 Is inflammatory bowel disease an independent and disease specific risk factor for thromboe 2004 Apr BACKGROUND: Patients with inflammatory bowel disease (IBD) are thought to be at increased risk of venous thromboembolism (TE). However, the extent of this risk is not known. Furthermore, it is not known if this risk is specific for IBD or if it is shared by other chronic inflammatory diseases or other chronic bowel diseases. AIMS: To compare the risk of TE in patients with IBD, rheumatoid arthritis, and coeliac disease with matched control subjects. PATIENTS AND METHODS: Study subjects answered a questionnaire assessing the history of TE, any cases of which had to be confirmed radiologically. A total of 618 patients with IBD, 243 with rheumatoid arthritis, 207 with coeliac disease, and 707 control subjects were consecutively included. All three patient groups were compared with control subjects matched to the respective group by age and sex. RESULTS: Thirty eight IBD patients (6.2%) had suffered TE. This was significantly higher compared with the matched control population with only 10 cases reported (1.6%) (p<0.001; odds ratio (OR) 3.6 (95% confidence interval (CI) 1.7-7.8)). Five patients with rheumatoid arthritis (2.1%) had suffered TE compared with six subjects (2.5%) in the control population matched to patients with rheumatoid arthritis (NS; OR 0.7 (95% CI 0.2-2.9)). TE had occurred in two patients with coeliac disease (1%) compared with four subjects (1.9%) in the control population matched to the coeliac disease group (NS; OR 0.4 (95% CI 0.1-2.5)). In 60% of TE cases in the IBD group, at least one IBD specific factor (active disease, stenosis, fistula, abscess) was present at the time TE occurred. CONCLUSIONS: IBD is a risk factor for TE. It seems that TE is a specific feature of IBD as neither rheumatoid arthritis, another chronic inflammatory disease, nor coeliac disease, another chronic bowel disease, had an increased risk of TE.
15497523 Noncardiogenic pulmonary edema in low-dose oral methotrexate therapy. 2004 Sep In the past two decades, low-dose methotrexate (MTX) has been widely used in the treatment of rheumatoid arthritis (RA). As adverse effects, various types of pulmonary toxicity have been reported with this therapy. We report a case of MTX-induced noncardiogenic pulmonary edema in a 35-year-old woman. MTX used in high dose for anti-cancer therapy is known to cause non-cardiogenic pulmonary edema. However, there are no previous reports of noncardiogenic pulmonary edema caused by low-dose MTX therapy. This report suggests that patients receiving oral weekly, low-dose MTX may be at risk for the development of noncardiogenic pulmonary edema.
15642153 Interleukin-7 deficiency in rheumatoid arthritis. 2005 Interleukin-7 (IL-7) is a stromal factor that is crucial for the development of T lymphocytes in humans and mice, and also B lymphocytes in mice. IL-7 can act as a T cell growth factor as well as a critical anti-apoptotic survival factor. The essential non-redundant role of this cytokine for T cell development in vivo is indicated by the phenotype of murine knockout models as well as by humans with a T-B+NK+ form of severe combined immunodeficiency (SCID) resulting from mutations in IL-7 receptor alpha chain. IL-7 deficiency has now been found in patients with rheumatoid arthritis, a finding that relates not only to the T-lymphocyte status in this disease but also to the ability of patients with rheumatoid arthritis to recover from therapy-induced lymphopenia.
15550533 Cost effectiveness of adalimumab in the treatment of patients with moderate to severe rheu 2005 Jul BACKGROUND: Societal decision makers increasingly emphasise their need for evidence based economic analyses to make reimbursement decisions. OBJECTIVE: To analyse the cost utility of adalimumab, on both incremental cost and incremental quality adjusted life years (QALYs), versus traditional disease modifying antirheumatic drugs and the other tumour necrosis factor (TNF) antagonists suitable for submission to the Swedish LFN (Pharmaceutical Benefit Board). METHODS: Swedish unit costs and treatment guidelines from a lifetime perspective were implemented. A mathematical model, incorporating data from seven trials, simulated the experiences of 10 000 hypothetical patients with moderate to severe rheumatoid arthritis (RA). The primary outcome measure-QALYs-was derived from utility values calculated from a relationship between the Health Assessment Questionnaire (HAQ) Disability Index (DI) and Health Utility Index-III (HUI-3) from adalimumab trial results. The model followed the progression of HAQ-DI through a number of treatments in a sequence accounting for mortality, drug and monitoring costs, and other direct costs. RESULTS: When using ACR50 as a response threshold for determining successful treatment, adalimumab plus methotrexate showed the greatest number of QALYs gained (2.3 from one study and 2.1 from the pooled results of two trials). The etanercept plus methotrexate strategy yielded QALY gains similar to the pooled adalimumab results. Except for the infliximab strategy, the costs results were between 35 000 and 42 000, a range normally considered cost effective in other European countries. CONCLUSION: Adalimumab appears to be cost effective for the treatment of moderate to severe RA. The results suggest that adalimumab is at least as cost effective as other TNF antagonists.
12707039 Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in 2003 May The aim of the study was to investigate the relationship between invasion and proliferation in rheumatoid arthritis synovial fibroblasts (RASFs). In vitro, RASFs, normal synovial fibroblasts (NSFs), and RASFs transformed with SV40 T-antigen (RASF(SV40)) were analyzed for the expression of cell surface markers (Thy1, VCAM-1, ICAM-1, CD40, CD44) and their proliferation by flow cytometry. Furthermore, colony-forming unit assays were performed and the expression of matrix metalloproteinases (MMP)-14 and cathepsin K mRNA were determined by real-time polymerase chain reaction. In vivo, in the severe combined immunodeficiency (SCID) mouse co-implantation model, RASFs, NSFs, and RASF(SV40) were tested for cartilage invasion, cellular density, and for their expression of the cell cycle-associated protein Ki67. In the SCID mouse co-implantation model, RASFs invaded significantly stronger into the cartilage than NSFs and RASF(SV40). Of note, RASF(SV40) cells formed tumor-like tissues, and the cellular density adjacent to the cartilage was significantly higher than in RASFs or NSFs. In turn, the proliferation marker Ki67 was strongly expressed in the SV40-transformed synoviocytes in SCID mice, but not in RASFs, and specifically not at sites of cartilage invasion. Using the colony-forming unit assay, RASFs and NSFs did not form colonies, whereas RASF(SV40) lost contact inhibition. In vitro, the proliferative rate of RASFs was low (4.3% S phase) in contrast to RASF(SV40) (24.4%). Expression of VCAM-1 was significantly higher, whereas of ICAM-1 was significantly lower, in RASFs than in RASF(SV40). CD40 was significantly stronger expressed in RASF(SV40), whereas CD44 and AS02 were present at the same degree in almost all synoviocytes. Expression of cathepsin K and matrix metalloproteinase-14 mRNA was significantly higher in RASFs than in the RASF(SV40). Our data demonstrate clearly that invasion of cartilage is mediated by activated RASFs characterized by increased expression of adhesion molecules, matrix-degrading enzymes, but does not depend on cellular proliferation, suggesting the dissociation of invasion and proliferation in RASFs.