Search tips
Search criteria

Results 1-16 (16)

Clipboard (0)

Select a Filter Below

Year of Publication
more »
Document Types
1.  Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications 
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).
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).
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.
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.
PMCID: PMC5032998  PMID: 25707877
2.  Expression and pathological effects of periostin in human osteoarthritis cartilage 
Osteoarthritis (OA) is one of the most common joint diseases in elderly people, however, the underlying mechanism of OA pathogenesis is not completely clear. Periostin, the extracellular protein, has been shown by cDNA array analysis to be highly expressed in OA, but its function is not fully understood. The purpose of this study was to examine the expression and function of periostin in human OA.
Human cartilage and synovia samples were used for the analysis of periostin expression and function. The human cartilage samples were obtained from the knees of patients undergoing total knee arthroplasty as OA samples and from the femoral bone head of patients with femoral neck fracture as control samples. Quantitative RT-PCR, ELISA, and immunohistochemistry were used for analysis of periostin expression in cartilage and synovia. Human primary chondrocytes isolated from control cartilage were stimulated by periostin, and the alteration of OA related gene expression was examined using quantitative RT-PCR. Immunocytochemistry of p65 was performed for the analysis of nuclear factor kappa B (NFκB) activation.
The periostin mRNA was significantly higher in OA cartilage than in control cartilage. Immunohistochemical analysis of periostin showed that the main positive signal was localized in chondrocytes and their periphery matrix near the erosive area, with less immunoreactivity in deeper zones. There was positive correlation between Mankin score and periostin immunoreactivity. The periostin expression was also detected in the fibrotic cartilage and tissue of subchondral bone. In cultured human chondrocytes, periostin induced the expression of interleukin (IL)-6, IL-8, matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, and nitric oxide synthase-2 (NOS2) in a dose- and time-dependent manner. The activation of NFκB signaling was recognized by the nuclear translocation of p65. Periostin-induced upregulation of these genes was suppressed by NFκB inactivation in chondrocytes.
Periostin was upregulated in OA cartilage, and it may amplify inflammatory events and accelerate OA pathology.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-015-0682-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4545863  PMID: 26289167
3.  Pachydermodactyly Treated with Tranilast in a Young Girl 
Case Reports in Orthopedics  2014;2014:132854.
Introduction. Pachydermodactyly is a rare disease with asymptomatic swelling of proximal interphalangeal joints. This disorder should be considered in the differential diagnosis of juvenile idiopathic arthritis or rheumatoid arthritis. However, pachydermodactyly is not well recognized by many orthopaedic surgeons and rheumatologists. Case Presentation. We report herein a case of a 13-year-old girl with pachydermodactyly. She presented to our clinic with symmetrical swelling of digits II through V without functional loss for the last 4 years. X-ray examination demonstrated no bone or joint destruction and magnetic resonance images showed only thickened skin tissues. No inflammatory signs were seen with laboratory blood tests. We reached a diagnosis of pachydermodactyly by exclusion. We had administered tranilast to her for 6 months and her symptom slightly improved. Conclusion. It is important to recognize pachydermodactyly and be able to differentiate it from other causes of PIP joint swelling such as rheumatoid arthritis, although pachydermodactyly is rare and benign. Physicians including orthopaedists and rheumatologists should make a prompt diagnosis to avoid unnecessary investigations and prevent the patient from receiving inappropriate treatment with steroids or cytotoxic agents. On the other hand, tranilast might be an effective drug to pachydermodactyly.
PMCID: PMC4140150  PMID: 25165590
4.  Repeat-dose intravenous tranexamic acid further decreases blood loss in total knee arthroplasty 
International Orthopaedics  2013;37(3):441-445.
Tranexamic acid (TXA) reduces blood loss in patients undergoing total knee arthroplasty (TKA). However, few studies have reported the optimum timing and dosage for administration of TXA. The purpose of this study was to evaluate the effect of repeat-dose TXA on blood loss during TKA and the necessity of autologous blood donation or postoperative autotransfusion.
We enrolled 78 patients with primary osteoarthritis undergoing cemented TKAs. Consecutive patients were divided into three groups, as follows: control group (n = 31), single-TXA group (n = 21) in whom TXA (1,000 mg) was intravenously administered 10 min before deflation of the tourniquet, and twice-TXA group (n = 26) in whom TXA (1,000 mg) was intravenously administered 10 min before deflation of the tourniquet and 3 h after the operation. We measured the volume of drained blood after the operation. Haemoglobin (Hb) levels were measured at days 1, 4 and 7 postoperation. Venous thromboembolic events (VTE) were screened using compression ultrasonography at enrollment and 1 and 7 days after operation.
The mean volume of drained blood after the operation was lower in the twice-TXA group than in the single-TXA (p < 0.001) and control (p < 0.0001) groups. No significant differences were observed in the incidence of VTE between these groups.
Administration of TXA twice reduced postoperative blood loss after TKA, and TXA was not associated with the risk of deep-vein thrombosis (DVT) or pulmonary embolism (PE). Further, administration of TXA twice may eliminate the need for blood transfusion during TKA.
PMCID: PMC3580084  PMID: 23371424
5.  In vivo kinematics of high-flex mobile-bearing total knee arthroplasty, with a new post-cam design, in deep knee bending motion 
International Orthopaedics  2012;36(12):2465-2471.
The objective of this study was to evaluate the in vivo knee kinematics to assess the available functional motion of the characteristic mobile-bearing prosthesis design and to examine whether the artificial joint would work in vivo according to its design concept.
We studied 14 knees (11 patients) implanted with the Vanguard RP Hi-Flex prosthesis. This prosthesis has a highly original form of post-cam called a PS saddle design with high compatibility, and with a rotating plate mobile-bearing mechanism. The cylinder-type post-cam is designed to enable contact in early flexion ranges, and to prevent paradoxical anterior femoral component movement. Each patient performed weight-bearing deep knee bending under fluoroscopic surveillance. Motion between each component including the polyethylene insert was analyzed using the 2D/3D registration technique.
The mean range of motion was 122.0°. The mean femoral component rotation for the tibial tray was 5.0°. No paradoxical anterior movement of the nearest point was confirmed between the femoral component and the tibial tray in the early flexion ranges. Initial contact of the post-cam was confirmed at a knee flexion angle of 33.8°. Subsequently, the wide contact of the post-cam was maintained until flexion reached 120° in all knees, but disengagement of the post-cam was observed in two knees when flexion was ≥130°.
The results of this study demonstrated that the prosthesis design generally works in vivo as intended by its design concept. The present kinematic data may provide useful information for improvement of high-flex type prostheses.
PMCID: PMC3508061  PMID: 23081946
6.  TNF inhibitors induce discoid fibrosis in the sublining layers of the synovium with degeneration of synoviocytes in rheumatoid arthritis 
Rheumatology International  2013;33(10):2473-2481.
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.
PMCID: PMC3782653  PMID: 23575549
Infliximab; Etanercept; Synovium; Histology; Fibrosis; Osteoclast
7.  Prevalence of gastroesophageal reflux disease symptoms and related factors in patients with rheumatoid arthritis 
Gastroesophageal reflux disease (GERD) is common in patients with many chronic diseases, but has not been well recognized in rheumatoid arthritis (RA). We investigated the prevalence of GERD symptoms in 278 outpatients with RA and their association with such clinical factors as age, sex, height, weight, body mass index, medications drugs, and functional status evaluated by the Modified Health Assessment Questionnaire (MHAQ). GERD symptoms were evaluated by Frequency Scale for the Symptoms of GERD (FSSG). The mean FSSG score for all patients was 5.6, and 82 patients were considered to have GERD symptoms (FSSG score ≥8), thus the overall prevalence of GERD symptoms was 29.5%. MHAQ score and height were significantly higher and lower, respectively, and prednisolone usage was significantly more in the patients with GERD symptoms than those without. These three clinical factors were also significantly associated with GERD symptoms by univariate logistic regression. Multivariate logistic regression analysis demonstrated that MHAQ was the only clinical factor related to GERD symptoms. In conclusion, the prevalence of GERD symptoms in RA patients was high and strongly associated with decreased functional status, suggesting that physicians should pay attention to GERD symptoms in RA management, especially for patients with low functional status.
PMCID: PMC3593137  PMID: 23525140
rheumatoid arthritis; gastroesophageal reflux disease; Frequency Scale for the Symptoms of GERD; Modified Health Assessment Questionnaire; quality of life
8.  Effect of posterior design changes on postoperative flexion angle in cruciate retaining mobile-bearing total knee arthroplasty 
International Orthopaedics  2010;35(5):689-695.
The Dual Bearing Knee (DBK) prosthesis is a new concept which has a mobile-bearing insert. In May 2001, the posterior femoral condyle design of the DBK was changed to become smaller and there was a posterior shift in the base of the insert dish (Hi-Flex). Between 1998 and 2004, 371 DBKs (112 Hi-Flex and 220 Standard) were performed by one surgical team. There was a significant difference in postoperative flexion angle between the Hi-Flex and Standard DBKs (117.0° and 111.3°; p = 0.001). The delta flexion angle in the Hi-Flex (−2.4°) was significantly increased compared with that in the Standard DBK (−9.6°) (p = 0.001). In the Hi-Flex DBK, the postoperative flexion angle (5.7°) and the delta flexion angle (7.2°) were significantly larger than for the Standard DBK (p < 0.001). These results suggest that the flexion is greater for a design with smaller posterior condyle prosthesis and with a posterior shift in the base of the insert dish in CR mobile-bearing TKA.
PMCID: PMC3080484  PMID: 20532884
9.  In vivo three-dimensional kinematics of total elbow arthroplasty using fluoroscopic imaging 
International Orthopaedics  2010;34(6):847-854.
Higher complication rates and lower survivorship are still seen for total elbow arthroplasties compared to total knee and hip arthroplasties. This is partly due to polyethylene wear of the articular surface induced by excessive articular contact stress during elbow motion. The aim of this study was to dynamically evaluate in vivo three-dimensional elbow motion after total elbow arthroplasty. Twelve patients (15 elbows) who underwent operation with the Osaka University Model Total Elbow System were analysed using X-ray fluoroscopic imaging and a two-dimensional/three-dimensional registration technique, which could accurately estimate the three-dimensional spatial position of components. Valgus/varus angle and rotation between humeral and ulnar components showed wide variations among patients. Elbows with valgus angle and internal rotation >10° could induce edge-loading of the articular surface. Component alignment, articular configuration, and soft-tissue balance can affect the kinematics of total elbow arthroplasty.
PMCID: PMC2989026  PMID: 20177892
10.  Case Report: Psoriatic Erythroderma with Bilateral Osseous Bridge Across the Acetabulum 
Abnormal reactions accompanied by bone formation in the osteoarticular region induced by long-term administration of etretinate have been reported. We treated a patient who received continuous treatment of psoriatic erythroderma with etretinate for 7 years, and who had an osseous bridge that extended across the acetabulum over the femur on both sides. The patient experienced a major gait disturbance and eventually was unable to walk. Functional gait was restored by resecting the ossified regions and radiotherapy. Histologic sections of the ossified lesions showed enchondral ossification in the ligament attachment site in the joint margin, with advancing ossification along the articular capsule; the pattern was similar to that in diffuse idiopathic skeletal hyperostosis. This is the first report of an osseous bridge associated with long-term administration of etretinate extending across the acetabulum over the femur on both sides.
PMCID: PMC2835593  PMID: 19657703
11.  Inhibitory effect of ribbon-type NF-κB decoy oligodeoxynucleotides on osteoclast induction and activity in vitro and in vivo 
In this study we examined the effect of ribbon-type (circular-type) NF-κB decoy oligodeoxynucleotides (RNODN) on osteoclast induction and activity. We extracted bone marrow cells from the femurs of rats and incubated non-adherent cells with receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). First, transfer efficiency into osteoclasts and their precursors, resistance to exonuclease, and binding activity of decoy to NF-κB were examined. Next, to examine the effect of RNODN on osteoclast induction and activity, osteoclast differentiation and pit formation assays were performed. RNODN were injected into the ankle joints of rats with collagen-induced arthritis. Joint destruction and osteoclast activity were examined by histological study. The resistance of RNODN to exonuclease and their binding activity on NF-κB were both greater than those of phosphorothionated NF-κB decoy oligodeoxynucleotides. The absolute number of multinucleate cells scoring positive for tartrate-resistant acid phosphatase was significantly decreased in the RNODN-treated group. The average calcified matrix resorbed area was significantly decreased in the RNODN-treated group. Histological study showed marked suppression of joint destruction and osteoclast activity by intra-articular injection of RNODN. These results suggest the inhibitory effect of RNODN on the induction and activity of osteoclasts. Direct intra-articular injection of RNODN into the joints may be an effective strategy for the treatment of arthritis.
PMCID: PMC1779370  PMID: 16813665
12.  Enhanced expression of mRNA for nuclear factor κB1 (p50) in CD34+ cells of the bone marrow in rheumatoid arthritis 
Bone marrow CD34+ cells from rheumatoid arthritis (RA) patients have abnormal capacities to respond to tumor necrosis factor (TNF)-α and to differentiate into fibroblast-like cells producing matrix metalloproteinase (MMP)-1. We explored the expression of mRNA for nuclear factor (NF)κB in RA bone marrow CD34+ cells to delineate the mechanism for their abnormal responses to TNF-α. CD34+ cells were purified from bone marrow samples obtained from 49 RA patients and 31 osteoarthritis (OA) patients during joint operations via aspiration from the iliac crest. The mRNAs for NFκB1 (p50), NFκB2 (p52) and RelA (p65) were examined by quantitative RT-PCR. The expression of NFκB1 mRNA in bone marrow CD34+ cells was significantly higher in RA than in OA, whereas there was no significant difference in the expression of mRNA for NFκB2 and RelA. The expression of NFκB1 mRNA was not correlated with serum C-reactive protein or with the treatment with methotrexate or oral steroid. Silencing of NFκB1 by small interfering RNA abrogated the capacity of RA bone marrow CD34+ cells to differentiate into fibroblast-like cells and to produce MMP-1 and vascular endothelial growth factor upon stimulation with stem cell factor, granulocyte-macrophage colony stimulating factor and TNF-α without influencing their viability and capacity to produce β2-microglobulin. These results indicate that the enhanced expression of NFκB1 mRNA in bone marrow CD34+ cells plays a pivotal role in their abnormal responses to TNF-α and, thus, in the pathogenesis of RA.
PMCID: PMC1526601  PMID: 16519794
13.  THR0921, a novel peroxisome proliferator-activated receptor gamma agonist, reduces the severity of collagen-induced arthritis 
THR0921 is a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent anti-diabetic properties. Because of the proposed role of PPARγ in inflammation, we investigated the potential of orally active THR0921 to inhibit the pathogenesis of collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by the injection of bovine type II collagen in complete Freund's adjuvant on days 0 and 21. Mice were treated with THR0921 (50 mg/kg/day) starting on the day of the booster injection and throughout the remaining study period. Both clinical disease activity scores as well as histological scores of joint destruction were significantly reduced in mice treated with THR0921 compared to untreated mice. Proliferation of isolated spleen cells, as well as circulating levels of IgG antibody to type II collagen, was decreased by THR0921. Moreover, spleen cell production of IFN-γ, tumor necrosis factor (TNF)-α and IL-1β in response to exposure to lipopolysaccharide or type II collagen was reduced by in vivo treatment with THR0921. Steady state mRNA levels of TNF-α, IL-1β, monocyte chemotactic protein-1 and receptor activator of nuclear factor κB ligand (RANKL) in isolated joints were all decreased in mice treated with THR0921. Finally, THR0921 inhibited osteoclast differentiation of bone marrow-derived cells stimulated with macrophage colony-stimulating factor and RANKL. In conclusion, THR0921 attenuates collagen-induced arthritis in part by reducing the immune response. As such, PPARγ may be an important therapeutic target for rheumatoid arthritis.
PMCID: PMC1526548  PMID: 16356194
14.  Total ankle replacement in rheumatoid arthritis 
International Orthopaedics  2003;28(2):123-126.
We reviewed 21 patients with rheumatoid arthritis who had a total ankle replacement between 1984 and 2000. The average follow-up was 72 (15–169) months. Clinical results were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) score. At the latest review, three ankles had been revised. Two ankles were excellent, seven good, three fair, and 12 poor. Eleven patients with 13 ankles had residual pain, with radiographs showing a high incidence of radiolucent lines. Migration of the tibial component was seen in 13 ankles and collapse of talus in nine. Although clinical results were poor, patient satisfaction was not.
PMCID: PMC3474485  PMID: 15224171
15.  VLA-4-dependent and -independent pathways in cell contact-induced proinflammatory cytokine production by synovial nurse-like cells from rheumatoid arthritis patients 
Arthritis Research  2002;4(6):R10.
Nurse-like stromal cell lines from the synovial tissue of patients with rheumatoid arthritis (RA-SNC) produce, on coculture with lymphocytes, large amounts of proinflammatory cytokines. In the present paper, we analyze the molecular events necessary for the induction of cytokine release from RA-SNC cells, and particularly the roles played by cell adhesion and the transmigration (also known as pseudoemperipolesis) of lymphocytes. For this purpose, the effects of various mAbs on the binding and transmigration of a human B-cell line, MC/car, were examined using a cloned RA-SNC line, RA-SNC77. To analyze the role of lymphocyte binding and transmigration on upregulated cytokine production by the RA-SNC77 cells, we used C3 exoenzyme-treated MC/car cells, which could bind to RA-SNC77 cells but could not transmigrate. Treatment with anti-CD29 or anti-CD49d mAb significantly reduced binding and transmigration of the MC/car cells. In contrast, the neutralizing anti-CD106/vascular cell adhesion molecule 1 mAb did not show any inhibitory effect. Likewise, none of the neutralizing mAbs against CD11a, CD18, CD44, CD49e, or CD54 showed significant effects. Binding of C3-treated or untreated MC/car cells to RA-SNC77 cells induced comparable levels of IL-6 and IL-8 production. In addition, the enhanced cytokine production by RA-SNC77 cells required direct lymphocyte contact via a very late antigen-4 (VLA-4)-independent adhesion pathway. These results indicate that, although both the VLA-4-dependent/vascular cell adhesion molecule 1-independent and the VLA4-independent adhesion pathways are involved in MC/car binding and subsequent transmigration, only the VLA4-independent adhesion pathway is necessary and sufficient for the enhanced proinflammatory cytokine production by RA-SNC77 cells. The transmigration process, which is dependent on Rho-GTPase, is not a prerequisite for this phenomenon.
PMCID: PMC153839  PMID: 12453313
cell adhesion; cytokine production; nurse cells; rheumatoid arthritis; transmigration
16.  Differentiation of monocytes into multinucleated giant bone-resorbing cells: two-step differentiation induced by nurse-like cells and cytokines 
Arthritis Research  2001;3(5):306-310.
Bone resorption in the joints is the characteristic finding in patients with rheumatoid arthritis (RA). Osteoclast-like cells are present in the synovial tissues and invade the bone of patients with RA. The characteristics of these cells are not completely known. In the work reported here, we generated these cells from peripheral-blood monocytes from healthy individuals. The monocytes were co-cultured with nurse-like cells from synovial tissues of patients with RA (RA-NLCs). Within 5 weeks of culture, the monocytes were activated and differentiated into mononuclear cells positive for CD14 and tartrate-resistant acid phosphatase (TRAP). These mononuclear cells then differentiated into multinucleated giant bone-resorbing cells after stimulation with IL-3, IL-5, IL-7, and/or granulocyte-macrophage-colony-stimulating factor. TRAP-positive cells with similar characteristics were found in synovial fluid from patients with RA. These results indicate that multinucleated giant bone-resorbing cells are generated from monocytes in two steps: first, RA-NLCs induce monocytes to differentiate into TRAP-positive mononuclear cells, which are then induced by cytokines to differentiate into multinucleated giant bone-resorbing cells.
PMCID: PMC64843  PMID: 11549372
monocytes; nurse cells; osteoclasts; rheumatoid arthritis; stromal cells

Results 1-16 (16)