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2.  Abnormal networks of immune response-related molecules in bone marrow cells from patients with rheumatoid arthritis as revealed by DNA microarray analysis 
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis that progresses to destruction of cartilage and bone. Bone marrow (BM) cells have been shown to contribute to this pathogenesis. In this study, we compared differentially expressed molecules in BM cells from RA and osteoarthritis (OA) patients and analyzed abnormal regulatory networks to identify the role of BM cells in RA.
Methods
Gene expression profiles (GEPs) in BM-derived mononuclear cells from 9 RA and 10 OA patients were obtained by DNA microarray. Up- and down-regulated genes were identified by comparing the GEPs from the two patient groups. Bioinformatics was performed by Expression Analysis Systemic Explorer (EASE) 2.0 based on gene ontology, followed by network pathway analysis with Ingenuity Pathways Analysis (IPA) 7.5.
Results
The BM mononuclear cells showed 764 up-regulated and 1,910 down-regulated genes in RA patients relative to the OA group. EASE revealed that the gene category response to external stimulus, which included the gene category immune response, was overrepresented by the up-regulated genes. So too were the gene categories signal transduction and phosphate metabolism. Down-regulated genes were dominantly classified in three gene categories: cell proliferation, which included mitotic cell cycle, DNA replication and chromosome cycle, and DNA metabolism. Most genes in these categories overlapped with each other. IPA analysis showed that the up-regulated genes in immune response were highly relevant to the antigen presentation pathway and to interferon signaling. The major histocompatibility complex (MHC) class I molecules, human leukocyte antigen (HLA)-E, HLA-F, and HLA-G, tapasin (TAP) and TAP binding protein, both of which are involved in peptide antigen binding and presentation via MHC class I molecules, are depicted in the immune response molecule networks. Interferon gamma and interleukin 8 were overexpressed and found to play central roles in these networks.
Conclusions
Abnormal regulatory networks in the immune response and cell cycle categories were identified in BM mononuclear cells from RA patients, indicating that the BM is pathologically involved in RA.
doi:10.1186/ar3364
PMCID: PMC3218904  PMID: 21679443
3.  Building up original evidence 
doi:10.1007/s00776-005-0985-6
PMCID: PMC2780617  PMID: 16437341
4.  Fondaparinux prevents venous thromboembolism after joint replacement surgery in Japanese patients 
International Orthopaedics  2007;32(4):443-451.
Venous thromboembolism (VTE) is an important complication of major orthopaedic surgery of the lower limbs. Fondaparinux, a synthetic pentasaccharide and highly selective inhibitor of activated Factor Xa, is the first in a new class of antithrombotic agents. To determine the optimal dose in Japanese patients, double-blind, placebo-controlled, dose-ranging studies of fondaparinux were conducted in patients undergoing total knee replacement (TKR) or total hip replacement (THR) surgery. Patients were randomly assigned to receive a once-daily subcutaneous injection of fondaparinux (0.75, 1.5, 2.5, or 3.0 mg) or placebo in Study 1 (TKR) and Study 2 (THR). In Study 1, the incidence of VTE was 65.3% in the placebo group and was 34.2%, 21.3%, 16.2%, and 9.5% in the groups receiving 0.75, 1.5, 2.5, and 3.0 mg fondaparinux respectively. In Study 2, the incidence of VTE was 33.8% in the placebo group and was 24.2%, 4.6%, 7.4%, and 14.4% in the 0.75, 1.5, 2.5, and 3.0 mg fondaparinux groups respectively. Dose–response effects were observed in both studies; however, no statistically significant differences in major bleeding events were found among any groups. Fondaparinux proved to be a potent anticoagulant with a favourable benefit-to-risk ratio in the prevention of VTE in these study patients.
doi:10.1007/s00264-007-0360-7
PMCID: PMC2532275  PMID: 17468868
5.  Proinflammatory role of amphiregulin, an epidermal growth factor family member whose expression is augmented in rheumatoid arthritis patients 
Background
The epidermal growth factor (EGF) and EGF receptor (EGFR) families play important roles in the hyperplastic growth of several tissues as well as tumor growth. Since synovial hyperplasia in rheumatoid arthritis (RA) resembles a tumor, involvement of the EGF/EGFR families in RA pathology has been implied. Although several reports have suggested that ErbB2 is the most important member of the EGFR family for the synovitis in RA, it remains unclear which members of the EGF family are involved. To clarify the EGF-like growth factors involved in the pathology of RA, we investigated the expression levels of seven major EGF-like growth factors in RA patients compared with those in osteoarthritis (OA) patients and healthy control subjects.
Methods
The expression levels of seven EGF-like growth factors and four EGFR-like receptors were measured in mononuclear cells isolated from bone marrow and venous blood, as well as in synovial tissues, using quantitative RT-PCR. Further evidence of gene expression was obtained by ELISAs. The proinflammatory roles were assessed by the growth-promoting and cytokine-inducing effects of the corresponding recombinant proteins on cultured fibroblast-like synoviocytes (FLS).
Results
Among the seven EGF-like ligands examined, only amphiregulin (AREG) was expressed at higher levels in all three RA tissues tested compared with the levels in OA tissues. The AREG protein concentration in RA synovial fluid was also higher than that in OA synovial fluid. Furthermore, recombinant human AREG stimulated FLS to proliferate and produce several proinflammatory cytokines, including angiogenic cytokines such as interleukin-8 and vascular endothelial growth factor (VEGF), in a dose-dependent manner. The VEGF mRNA levels in RA synovia and VEGF protein concentrations in RA synovial fluid were significantly higher than those in the corresponding OA samples and highly correlated with the levels of AREG.
Conclusion
The present findings suggest that AREG functions to stimulate synovial cells and that elevated levels of AREG may be involved in the pathogenesis of RA.
doi:10.1186/1476-9255-5-5
PMCID: PMC2396620  PMID: 18439312
6.  Mesenchymal stromal cells. Nurse-like cells reside in the synovial tissue and bone marrow in rheumatoid arthritis 
A major question concerning the immunopathology of rheumatoid arthritis is why the disease is localized to particular joints. A possible explanation could be the presence within the synovium of cells that foster inflammation or easy accessibility of the synovium to migratory disease enhancing cells. Within both the bone marrow and the synovium, fibroblastic stromal cells play an important role in supporting the differentiation and survival of normal cells, and also contribute to the pathologic processes. Among fibroblastic stromal cells in synovial tissue and bone marrow, nurse-like cells are a unique population having the specific capacity to promote pseudoemperipolesis (adhesion and holding beneath) of lymphocytes, and also the ability to promote the growth and function of some populations of lymphocytes and monocytes. Nurse-like cells could therefore contribute to the immunopathogenesis of rheumatoid arthritis, and may contribute to the localization of inflammation within specific joints. The present review considers the evidence that supports these possibilities.
doi:10.1186/ar2105
PMCID: PMC1860058  PMID: 17306036
7.  Surface-based registration accuracy of CT-based image-guided spine surgery 
European Spine Journal  2004;14(3):291-297.
Registration is a critical and important process in maintaining the accuracy of CT-based image-guided surgery. The aim of this study was to evaluate the effects of the area of intraoperative data sampling and number of sampling points on the accuracy of surface-based registration in a CT-based spinal-navigation system, using an optical three-dimensional localizer. A cadaveric dry-bone phantom of the lumbar spine was used. To evaluate registration accuracy, three alumina ceramic balls were attached to the anterior and lateral aspects of the vertebral body. CT images of the phantom were obtained (1-mm slice thickness, at1-mm intervals) using a helical CT scanner. Twenty surface points were digitized from five zones defined on the basis of anatomical classification on the posterior aspects of the target vertebra. A total of 20 sets of sampling data were obtained. Evaluation of registration accuracy accounted for positional and rotational errors. Of the five zones, the area that was the largest and easiest to expose surgically and to digitize surface points was the lamina. The lamina was defined as standard zone. On this zone, the effect of the number of sampling points on the positional and rotational accuracy of registration was evaluated. And the effects of the additional area selected for intraoperative data sampling on the registration accuracy were evaluated. Using 20 surface points on the posterior side of the lamina, positional error was 0.96 mm±0.24 mm root-mean-square (RMS) and rotational error was 0.91°±0.38°RMS. The use of 20 surface points on the lamina usually allows surgeons to carry out sufficiently accurate registration to conduct computer-aided spine surgery. In the case of severe spondylosis, however, it might be difficult to digitize the surface points from the lamina, due to a hypertrophic facet joint or the deformity of the lamina and noisy sampling data. In such cases, registration accuracy can be improved by combining use of the 20 surface points on the lamina with surface points on other zones, such as on the both sides of the spinous process.
doi:10.1007/s00586-004-0797-y
PMCID: PMC3476741  PMID: 15526221
Surgical navigation; Spine surgery; Computed tomography; Accuracy
8.  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.
doi:10.1186/ar1915
PMCID: PMC1526601  PMID: 16519794
9.  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.
doi:10.1007/s00264-003-0512-3
PMCID: PMC3474485  PMID: 15224171
10.  Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia 
The Journal of Cell Biology  2004;165(3):433-445.
Biochemical experiments have shown that Smad6 and Smad ubiquitin regulatory factor 1 (Smurf1) block the signal transduction of bone morphogenetic proteins (BMPs). However, their in vivo functions are largely unknown. Here, we generated transgenic mice overexpressing Smad6 in chondrocytes. Smad6 transgenic mice showed postnatal dwarfism with osteopenia and inhibition of Smad1/5/8 phosphorylation in chondrocytes. Endochondral ossification during development in these mice was associated with almost normal chondrocyte proliferation, significantly delayed chondrocyte hypertrophy, and thin trabecular bone. The reduced population of hypertrophic chondrocytes after birth seemed to be related to impaired bone growth and formation. Organ culture of cartilage rudiments showed that chondrocyte hypertrophy induced by BMP2 was inhibited in cartilage prepared from Smad6 transgenic mice. We then generated transgenic mice overexpressing Smurf1 in chondrocytes. Abnormalities were undetectable in Smurf1 transgenic mice. Mating Smad6 and Smurf1 transgenic mice produced double-transgenic pups with more delayed endochondral ossification than Smad6 transgenic mice. These results provided evidence that Smurf1 supports Smad6 function in vivo.
doi:10.1083/jcb.200311015
PMCID: PMC2172180  PMID: 15123739
chondrocyte; hypertrophy; osteopenia; dwarfism; transgenic mice
11.  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
12.  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
13.  Synovial stromal cells from rheumatoid arthritis patients attract monocytes by producing MCP-1 and IL-8 
Arthritis Research  2001;3(2):118-126.
Macrophages that accumulate in the synovium of rheumatoid arthritis patients play an important role in the pathogenesis of this inflammatory disease. However, the mechanism by which macrophages are attracted into the inflamed synovium and accumulate there has not been completely delineated. The results of this study show that rheumatoid arthritis synovial stromal cells produce the chemokines monocyte chemotactic protein-1 and IL-8, and these have the capacity to attract peripheral monocytes. These results suggest that one of the mechanisms by which macrophages accumulate in the inflamed synovium is by responding to the chemokines produced locally.
PMCID: PMC17828  PMID: 11178119
chemokine; monocyte; rheumatoid arthritis
14.  Stem length and canal filling in uncemented custom-made total hip arthroplasty 
International Orthopaedics  1999;23(4):219-223.
Abstract 
We reviewed 60 custom-made femoral components of two different lengths : 125 mm (group A) and 100 mm (group B), in order to investigate the relationship between stem length and canal filling in uncemented custom-made total hip arthroplasty. There were no statistical differences between the two groups in age, gender, height, body weight, canal flare index, or bowing angle of the femur. Postoperatively there was no statistical difference between the two groups in the proximal canal filling, but significant difference in the distal canal filling (75.5% vs 85.8% on the anteroposterior view and 76.0% vs 82.5% in the lateral view, P<0.001). The distal canal filling inversely correlated with the ratio of the proximal portion and the distal portion of the stem curvature on the lateral view (lateral curve ratio of the stem, P=0.002). We conclude that superior filling at both the proximal and the distal levels can be obtained by using 100-mm custom made components with a small lateral curve ratio.
doi:10.1007/s002640050355
PMCID: PMC3619735  PMID: 10591939
16.  Role of CDMP-1 in Skeletal Morphogenesis: Promotion of Mesenchymal Cell Recruitment and Chondrocyte Differentiation  
The Journal of Cell Biology  1999;144(1):161-173.
Cartilage provides the template for endochondral ossification and is crucial for determining the length and width of the skeleton. Transgenic mice with targeted expression of recombinant cartilage-derived morphogenetic protein-1 (CDMP-1), a member of the bone morphogenetic protein family, were created to investigate the role of CDMP-1 in skeletal formation. The mice exhibited chondrodysplasia with expanded cartilage, which consists of the enlarged hypertrophic zone and the reduced proliferating chondrocyte zone. Histologically, CDMP-1 increased the number of chondroprogenitor cells and accelerated chondrocyte differentiation to hypertrophy. Expression of CDMP-1 in the notochord inhibited vertebral body formation by blocking migration of sclerotome cells to the notochord. These results indicate that CDMP-1 antagonizes the ventralization signals from the notochord. Our study suggests a molecular mechanism by which CDMP-1 regulates the formation, growth, and differentiation of the skeletal elements.
PMCID: PMC2148125  PMID: 9885252
bone morphogenetic protein family; cartilage; ectopic expression; skeletal abnormalities; transgenic mice
17.  Membrane Fas Ligand Kills Human Peripheral Blood T Lymphocytes, and Soluble Fas Ligand Blocks the Killing  
The Journal of Experimental Medicine  1997;186(12):2045-2050.
It has been believed that the Fas expressed on human peripheral blood T cells (PBT) is nonfunctional, because these cells are insensitive to agonistic anti-Fas/Apo-1 mAbs that efficiently kill in vitro–activated T cells and many Fas-expressing cell lines. Here, we demonstrate that membrane-bound Fas ligand (FasL) kills both fresh and in vitro–activated PBT, indicating that the Fas expressed on fresh PBT is functional. In contrast, soluble FasL kills only the latter. Naive T cells in umbilical cord blood do not express Fas, but can be induced to express Fas by IFN-γ or by a combination of IL-2 and anti-CD28 mAb, after which they acquire sensitivity to membrane but not to soluble FasL. Soluble FasL inhibited the killing of fresh PBT by membrane FasL. These results indicate that the shedding of FasL from the membrane is a mechanism for downregulating at least part of its killing activity.
PMCID: PMC2199173  PMID: 9396774
18.  Surgical Treatment for Skeletal Metastases From Soft Tissue Sarcomas: Experience With 23 Lesions in 20 Patients 
Sarcoma  1998;2(2):107-114.
Purpose. This paper reports the procedures and the clinical results of a series of surgical treatments for skeletal metastases from soft tissue sarcomas.
Subjects and methods. Surgical treatment of metastatic bony lesions from soft tissue sarcomas has been carried out over a 20 year period (1975–1996). Thirty-two patients developed skeletal metastases from soft tissue sarcomas, and 20 of these cases received surgical treatment. The 23 metastatic bony lesions in these 20 patients were treated using the following surgical approaches: wide resection with prosthetic replacement in five lesions, wide or marginal resection without reconstruction in four lesions, intramedullarly nailing with curettage and methylmethacrylate cementation in four lesions, marginal resection of vertebral body with replacement by a ceramic prosthesis in three lesions, laminectomy in three lesions, intramedullarly nailing in two lesions, and curettage in two lesions.
Results. Relief of pain was achieved in 17 of the 20 patients. The ambulatory status of the patients with metastasis in the lower extremity or periacetabular region was significantly improved in nine of 10 cases. Seventeen patients died of disease, with a mean survival period of 17.9 months after surgery for metastasis.
Discussion. Although surgical treatment for skeletal metastases from soft tissue sarcomas cannot save the life of the patient, it can be of value in improving their well-being and overall quality of life. In these cases, surgical intervention may be more frequently indicated than in tumors with an osteoblastic or mixed pattern.
doi:10.1080/13577149878064
PMCID: PMC2395386  PMID: 18521241

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