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Objective Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Methods Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4-treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA). Results Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFα induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. Conclusion A positive feedback loop involving sSema4D/IL-6 and TNFα/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti-Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA. [ABSTRACT FROM AUTHOR]

Objective. It is often that patients with rheumatoid arthritis (RA) who require ankle surgeries already have the degeneration of talocalcaneal joints. When talocalcaneal joint was fused, whether operatively or spontaneously, ankle kinematics would be affected. The purpose of this paper was to study in vivo kinematics of mobile-bearing total ankle replacement (TAR) in rheumatoid ankle with concomitant talocalcaneal arthrodesis or with preexisting spontaneous talocalcaneal fusion. Methods. Thirteen TARs in ten patients with RA, in whom talocalcaneal joints had already been fused spontaneously or surgically, were studied. Fluoroscopic images were obtained while each patient was walking with full weightbearing on the implanted ankle. Thereafter tibio-talar motion was analyzed by 2D/3D registration technique. Results. Average tibio-talar motion was 4.0 ± 5.3° for plantarflexion and 6.6 ± 0.3° for dorsiflexion. Average range of internal/external rotation, inversion/eversion and AP translation was 3.8 ± 1.3°, 2.7 ± 1.0° and 1.6 ± 0.6 mm, respectively. Conclusions. Mobility of mobile-bearing TAR with talocalcaneal fusion was small during the stance phase of gait, but clinically measured ROM was mostly preserved. The movements of internal/external rotation and AP translation were allowed to a certain degree, but not of inversion/eversion. Even though the movement of inversion/eversion is limited, talocalcaneal arthrodesis could be accompanied with mobile-bearing TAR in rheumatoid ankles. [ABSTRACT FROM AUTHOR]

Objective. Plasmacytoid dendritic cells (pDCs) have been found to be accumulated in synovial tissues in rheumatoid arthritis (RA). Since pDCs originate from bone marrow (BM), we explored the differentiation of pDC in BM in RA and osteoarthritis (OA). Methods. BM mononuclear cells (BMMNCs) of the posterior ileac crest from 25 RA patients and 22 OA patients were examined for the expression of BDCA2 and CD34 by flow cytometry. The degree of synovial proliferation was assessed on light microscopy in 10 of 25 RA patients. Results. There were no significant differences in percentages of CD34 + cells or BDCA2 + cells within BMMNC between RA and OA. However, RA BMMNC contained higher percentages of BDCA2 + CD34 + cells (pre-pDCs) than OA BMMNCs. Accordingly, percentages of BDCA2 + CD34+ cells within BM CD34 + cells were significantly higher in RA than in OA. Finally, the percentages of BDCA2 + CD34+ cells within BM CD34 + cells were significantly correlated with the degree of synovial proliferation in RA. Conclusion. These results indicate that the generation of pre-pDC from BM CD34 + cells is increased in RA compared with OA. Moreover, the data suggest that the increased output of pDC from BM might be involved in the synovial proliferation in RA. [ABSTRACT FROM AUTHOR]

Aim Celecoxib ( CEL), a selective cyclooxygenase-2 ( COX-2) inhibitor, has been reported to suppress osteoclastogenesis in vitro, reduce levels of bone resorption markers in ovariectomized ( OVX) mice, and prevent bone destruction in rheumatoid arthritis ( RA) model mice; however, no clinical data has been reported. Here, we prospectively evaluated the changes in bone turnover markers in RA patients who switched from nonsteroidal anti-inflammatory drugs ( NSAIDs) to CEL, to examine the effects of selective COX-2 inhibitor on bone metabolism. Methods RA patients who had been treated with NSAIDs for more than 12 weeks were switched to CEL (400 mg/day) without any other changes in previously prescribed medications. Urinary type I collagen cross-linked N-telopeptide (u NTX), serum bone alkaline phosphatase ( BAP), C-reactive protein ( CRP), erythrocyte sedimentation rate ( ESR) and matrix metalloproteinase-3 ( MMP-3) were evaluated before switching to CEL and 16 weeks later. Results Significant reductions in u NTX, a bone resorption marker, were observed in 60 female patients ( P = 0.042), especially in 52 postmenopausal women ( P = 0.033). However, u NTX level did not significantly change in premenopausal women or in men. There were no significant changes in BAP, a bone formation marker. CRP significantly decreased ( P = 0.007), while ESR and MMP-3 were unchanged. Conclusion CEL reduced the levels of a bone resorption marker in postmenopausal RA patients, suggesting that this drug may attenuate the accelerated osteoclastic bone resorption associated with menopause. [ABSTRACT FROM AUTHOR]

We determined the characteristic features of synovial tissues of rheumatoid arthritis (RA) patients treated by TNF inhibitors in order to delineate their mechanism of action. Synovial tissues were obtained during the joint surgical operations from 12 RA patients who had been treated with TNF inhibitors in addition to disease modifying antirheumatic drugs (DMARDs) for at least 5 months (5-25 months) (RA-TNFinh), and from 12 RA patients who had been treated with DMARDs alone (RA-DMARD), and were evaluated under light microscopy. There were no significant differences in disease duration, serum CRP levels, DAS28, Steinbrocker's stages on X-ray and treatment regimen except for TNF inhibitors between RA-TNFinh and RA-DMARD. The most prominent changes in the synovium from RA-TNFinh were discoid fibrosis in the subliming layers of the synovium with degeneration and detachment of synoviocytes and marked decrease in vasculatures. There was no significant difference in these synovial features between RA patients with infliximab and those with etanercept. Interestingly, appearance of osteoclasts was observed in RA-TNFinh (3 out of 12 patients) and in RA-DMARD (1 out of 12 patients). These results indicate that not only infliximab, but etanercept might have direct actions on synovial cells in the deep lining layers of the synovium, leading to the discoid fibrosis thereof. Moreover, the data confirm that the deep lining or sublining layers of the synovium are the most important portions that steer the disease process of RA synovitis. [ABSTRACT FROM AUTHOR]

The existence of inorganic polyphosphates [poly(P)] in human cells has been demonstrated. In osteoblasts, it is suggested that the concentration of cellular poly(P) is relatively high. In this study, we examined whether poly(P) accelerates the differentiation of human mesenchymal stem cells (hMSCs) from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) into osteoblastic cells. Alkaline phosphatase (ALP) activity was induced by poly(P) in hMSCs from both OA and RA. In Alizarin Red S and osteocalcin EIA, there was a significant difference between the control and poly(P) group. In real-time PCR, there was a significant difference in ALP, collagen type 1A, osteocalcin, and bone sialoprotein between the control and poly(P) group. Our findings suggest that poly(P) have the potent role of differentiating hMSCs into osteoblastic cells at the early and later stages of osteoblastic differentiation. [ABSTRACT FROM AUTHOR]

The objective of the present study was to elucidate the mode of rheumatoid arthritis shoulder destruction. The study included 402 shoulders from 201 patients with rheumatoid arthritis. Plain radiographic findings were used to assess and statistically analyze the severity of the glenohumeral joint destruction (GHD) and greater tuberosity destruction (GTD). For both GHD and GTD scores, a statistically significant correlation was found between the left and right sides and also between the GHD and GTD scores within the same shoulder. However, 97 shoulders of 67 patients showed a heterogeneous pattern. An interesting finding was that no patients showed a combination of the GHD type plus the GTD type. Shoulders with rheumatoid arthritis showed statistically significant symmetry and uniform destruction. Even if they showed heterogeneous destruction, there were no cases of a different pattern of heterogeneity on the opposite side. The mode of destruction was not always definite, however. [Copyright &y& Elsevier]

The purpose of this study was to analyze the skeletal alignment of the hindfoot valgus deformity in patients with rheumatoid arthritis using bone models reconstructed from three-dimensional computerized tomography data. Computed tomography was performed on 21 feet of patients with rheumatoid arthritis, and magnetic resonance imaging was taken of 10 normal feet of eight volunteers. An image processing system was used to create bone models and analyze the three-dimensional displacement of the calcaneus, talus, navicular, and cuboid bones. With a standard coordinate system in the distal tibia and a local coordinate system in each bone of the hindfoot, three rotational parameters and three translational parameters were used to evaluate the relative displacement. The talus showed plantar flexion. Both the calcaneus and navicular bones had valgus and lateral shift displacements. However, the cuboid had no displacement relative to the calcaneus, and the navicular showed no displacement relative to the cuboid. The calcaneus, navicular, and cuboid bones have the same pattern of deformity in patients with rheumatoid arthritis. This three-dimensional image-based technique successfully quantified the hindfoot valgus deformity resulting from rheumatoid arthritis and is beneficial for better understanding the deformity pathomechanism. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [ABSTRACT FROM AUTHOR]

The aim of this study was to elucidate the utility and limitation of gadopentetate (Gd)-enhanced MRI as a method for evaluating the anterior cruciate ligament (ACL) in the rheumatoid arthritis (RA) knee, using both surgical macro findings and histological findings to ascertain the pathological condition of the affected knee. Thirty-six knees of 25 RA patients were studied in this study. Four imaging protocols were employed: protocol A, T1-weighted and T2-weighted sagittal images; protocol B, T1-weighted sagittal image, after infusion of Gd-DTPA (0.2 mmol/kg, i.v.); protocol C, T1-weighted angled coronal image, parallel to the ACL; and protocol D, T1-weighted angled coronal image, parallel to the ACL, after infusion of Gd-DTPA. Sagittal image was determined as previously described. Angle coronal image was newly determined as coronal image parallel to the ACL. Surgical and MRI findings of the ACL were classified into four types: Type I (normal group) indicated that the thickness of the ACL was almost normal, adequate tension was maintained (surgical findings),and the ACL had thick and a more complex appearance with a homogeneous signal intensity and well-defined borders (MRI findings). Type II (degenerated group): the ACL had degenerated and tension was reduced (surgical findings), and the ACL had thin and a more complex appearance with a less homogeneous signal intensity and less well-defined borders. This appearance was more evident on Type II than Type I (MRI findings). Type III (ruptured group): the parenchyma of the ACL remained but lacked continuity (surgical findings), and the ACL appeared as partial lack of low signal intensity (MRI findings). Type IV (absent group): the parenchyma of the ACL was practically absent (surgical findings), and the ACL appeared as complete lack of signal low signal intensity (MRI findings). The concordance rate between surgical and MRI findings was investigated. Moreover, we investigated the extent to which histological changes of the ACL could be discriminated using MRI. In RA knees, the overall concordance rate between surgical and MRI findings was 41.7% under imaging protocol A. The overall rate improved up to 69.4% under imaging protocol B. But the overall rate dropped to 36.1% under imaging protocol C. The overall rate improved up to 83.3% under imaging protocol D. Especially, significant differences between imaging protocols A and B ( p<0.05), and imaging protocols C and D ( p<0.01), with respect to ACL degenerated group, were recognized. But significant differences between imaging protocols A and C, and imaging protocols B and D, with respect to ACL degenerated group, were not recognized. The concordance rate between histological and MRI findings was 41.7% in ACL normal group, and 61.5% in ACL degenerated group. The concordance rate between surgical and MRI findings was 100% in ACL normal group, and 78.9% in ACL degenerated group. There was a significant difference in the concordance rates between histological, surgical, and MRI findings in normal group ( p<0.05). The results of this study suggested that with Gd-enhanced MRI, the degree of synovial proliferation around the ACL and the degree of degradation of the ACL in the RA knee can be evaluated more accurately than with conventional MRI; however, in RA knees with severe synovial proliferation, it may be difficult to discriminate between the invasive synovium going into the ligament from synovium surrounding the ligament. This may be a limitation of Gd-enhanced MRI at present. In the clinical setting, the present imaging technique does allow the ligament to be evaluated to a certain degree, and may prove useful in the evaluation of temporal changes in the RA knee. [ABSTRACT FROM AUTHOR]

A systematic review of randomized controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients was conducted to evaluate the risk of NSAID-induced adverse reactions. Double-blind, randomized, controlled trials with 6-week treatments for RA patients were included in the study. The endpoints for the analysis included any adverse reactions, digestive adverse reactions, and upper gastrointestinal (GI) adverse reactions. A fixed-effect model was used for estimation of the risk. Time-to-event analysis of the incidence of adverse reactions was also conducted. A total of 28 trials was included for the analysis, and a total of 30 NSAIDs were used in the trials. The proportion of patients who experienced any adverse reaction was as follows: piroxicam 18.9% (3 trials), diclofenac 18.8% (4 trials), indomethacin 22.1% (14 trials), and aspirin 25.0% (4 trials). The proportion of patients who experienced digestive adverse reactions was as follows: piroxicam 10.2%, diclofenac 10.6%, indomethacin 13.1%, and aspirin 14.1%. Most withdrawals due to adverse reaction occurred during the first 3 weeks after administration of the NSAID. Although the risk of NSAID-induced adverse reaction was different from drug to drug, the risk of adverse reaction was clinically significant. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate the expression of tumor necrosis factor-α converting enzyme (TACE) in the synovium and subchondral bone region of patients with rheumatoid arthritis (RA) and to determine the contribution of the enzyme to the pathogenesis of RA. Joint tissues were obtained during total knee arthroplasty from patients with RA and osteoarthritis (OA). The expression of TACE and TNF-α mRNA was detected by in situ hybridization. Characterization of TACE expressing cells was performed by immunohistochemistry using serial sections. We found that TACE mRNA was expressed in both synovium and subchondral bone region and co-localized with TNF-α mRNA in RA. On the other hand, TACE mRNA expression was scarcely detectable in OA samples. TACE was expressed in mononuclear cells, such as CD3 and CD14 positive cells in RA samples. In conclusion, the expression of TACE is up-regulated in the rheumatoid synovium and subchondral bone region, and the results in this study demonstrate that TACE may be involved and play a role in the pathogenesis of RA. [ABSTRACT FROM AUTHOR]

IL-6 and tumor necrosis factor (TNF)-α have been proven to play an important role in the development of rheumatoid arthritis (RA). It is well known that TNF-α induces IL-6 production from synovial cells as well as their proliferation. The effect of IL-6 on synovial cells, however, is not clear. An in vitrostudy was performed to determine the effect of IL-6 on the proliferation of synovial cells. Fibroblastic synovial cells isolated from the synovial tissues of eight RA patients were employed after the third to sixth passages. IL-6 in the presence of soluble IL-6 receptor (sIL-6R) inhibited the proliferation of synovial cells in a dose-dependent manner in seven cases without increasing the number of necrotic or apoptotic cells, while TNF-α increased synovial cell proliferation in all cases. The inhibitory effect of IL-6 was observed only in the presence of sIL-6R although small amounts of IL-6R were detected in these cells by RT-PCR analysis. However, anti-IL-6R or anti-gp130 mAb treatment increased spontaneous growth of synovial cells in all eight cases, suggesting that endogenous IL-6 and a small amount of IL-6R expressed in synovial cells suppressed their growth without exogenous IL-6 or sIL-6R. In addition, the IL-6–sIL-6R complex reduced the TNF-α-induced proliferation of synovial cells while TNF-α induced their IL-6 production. These data suggest that IL-6 may act as a negative feedback factor for TNF-α-induced synovial cell growth. [ABSTRACT FROM PUBLISHER]

Objective. To evaluate the osteoblastic differentiation of human mesenchymal stem cells (hMSCs) in patients with RA. Methods. Heparinized bone marrow aspirate was obtained from patients with OA and RA. Mononuclear cells were cultured for 2 weeks and a colony-forming assay was performed. The phenotype of cells was analysed by flow cytometry. Passage 2 cells were cultured with β-glycerophosphate (bGP) in the control group and bGP, ascorbic acid and dexamethasone in the differentiation group. After 2 weeks, ALP staining and activity were performed. After 3 weeks, Alizarin Red S assay was performed. Total RNA was extracted from cells cultured for 2 and 3 weeks. Gene expression of bone formation factor was examined by real-time PCR. Results. The phenotype of cells was identical in both OA and RA and the content was thought to be hMSCs. The results of ALP activity and Alizarin Red S assay showed higher levels in the differentiation group for both OA and RA samples compared with the control group. The results of a colony-forming assay were identical in both OA and RA samples. Gene expression in the differentiation group was higher than in the control group in both OA and RA samples. There was no significant difference between OA and RA samples in all experiments. Conclusion. The function of osteoblastic differentiation of hMSCs is similar between OA and RA. [ABSTRACT FROM AUTHOR]

Abstract: We have recently demonstrated that bone marrow CD34+ cells from rheumatoid arthritis (RA) patients displayed abnormal capacities to respond to TNF-α and to differentiate into fibroblast-like cells producing MMP-1 (type B synoviocyte -like cells). The current study examined the effects of representative potent disease-modifying antirheumatic drugs, including bucillamine (BUC) and methotrexate (MTX) on the in vitro generation of fibroblast-like cells from RA bone marrow CD34+ cells. CD34+ cells purified from bone marrow specimens of 8 patients with active RA were cultured in the presence or absence of pharmacologically attainable concentrations of intramolecular disulfide form of bucillamine (BUC-ID, 3 μM), a major metabolite of BUC or MTX (20 nM). After incubation for 28 days, the generation of fibroblast-like cells was assessed under phase-contrast light microscopy and the concentrations of MMP-1 and VEGF in the culture supernatants were measured by ELISA. BUC-ID, but not MTX, significantly suppressed the generation of fibroblast-like cells from RA bone marrow CD34+ cells stimulated with SCF, GM-CSF and TNF-α (p =0.024 as determined by Wilcoxon signed rank test). Accordingly, BUC-ID, but not MTX, significantly suppressed the production of MMP-1 (p =0.017) and VEGF (p =0.017) by RA bone marrow CD34+ cells, without inhibition of β2-microglobulin production. These results demonstrate that BUC-ID, but not MTX, is a potent inhibitor of differentiation of fibroblast-like cells from RA bone marrow CD34+ cells. Since MTX, but not BUC, has been previously shown to influence on type A synoviocytes, the data provide rationale of combination of BUC and MTX in the treatment of RA. [Copyright &y& Elsevier]

Abstract: Circuit of chronic inflammation in the joints of rheumatoid arthritis (RA) starts from the production of inflammatory cytokines by fibroblast-like synoviocytes (FLS) stimulated by TNFα produced by inflammatory cells mainly composed of macrophages. In this context, TNFα/NF-κB pathway plays an essential role for the transcription of pro-inflammatory cytokines. Here we show that the kinetics of pro-inflammatory cytokine genes induced by TNFα in FLS from RA was synchronized with that of A20, ABIN1, and ABIN3 that have been thought as negative regulators for NF-κB activation. Furthermore, based on this finding, we could tentatively categorize the RA-FLS into two groups; TNFα low-responder and high-responder FLS. The high responders that have abundant mRNA levels of NF-κB inhibitory molecules were also accompanied with the marked induction of the pro-inflammatory cytokines by the stimulation with TNFα. The low responders RA-FLS did not show this property, nor did FLS from osteoarthritis. Phosphorylation dependent degradation of IκBα as well as NF-κB activation upon stimulation with TNFα was significantly enhanced in the high-responder FLS lines. Surprisingly, single transfection of each NF-κB inhibitor was enough to facilitate the transcription of pro-inflammatory cytokines, suggesting that there is an unknown pro-inflammatory function for A20 and ABIN family proteins in RA-FLS. [Copyright &y& Elsevier]

Abstract: We examined the capacities of bone marrow (BM) plasmacytoid dendritic cells (pDC) to differentiate into type B synoviocyte-like cells. BM aspiration samples were obtained from 24 rheumatoid arthritis (RA) patients and 19 osteoarthritis (OA) patients during joint operations from the iliac crest. CD34+ cells and pDC purified from BM mononuclear cells were cultured with or without SCF, GM-CSF, and TNF-α for 2–4weeks. RA BM pDC as well as OA BM pDC comparably differentiated into fibroblast-like cells (FLC), expressing cadherin-11 and producing MMP-1, especially in the presence of TNF-α. Of note, depletion of BDCA4+ pDC from RA BM CD34+ cells significantly diminished their capacities to differentiate into FLC, which were restored by addition of BDCA4+cells in a dose–response manner. These results indicate that pDC is one of the progenitors of type B synoviocytes, suggesting that BM pDC might be involved in the pathogenesis of RA and OA. [Copyright &y& Elsevier]

Abstract: In inflammatory arthritis such as RA, osteoclastic activity is severely enhanced. GM-CSF was reportedly elevated in synovial fluid, but is a strong inhibitor of osteoclastogenesis; here lies a contradiction. Our objective was to examine what type of osteoclasts generate and resorb bone with resistance to GM-CSF in an inflammatory joint. Monocyte-derived cells generated in GM-CSF were morphologically and immunophenotypically different from both the conventional DC and macrophage. They could differentiate into osteoclasts in the presence of RANKL + M-CSF, acquiring a stronger osteoclastic activity under TNF treatment. Furthermore, their differentiation was not inhibited by GM-CSF, while monocyte-derived osteoclast differentiation was completely inhibited. The resorption was suppressed by GM-CSF, and the existence of another osteoclastic pathway has been suggested. Our findings indicate another type of osteoclast exists in inflammatory arthritis. [Copyright &y& Elsevier]