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Search Results: 1 - 10 of 212 matches for " Kusuki Nishioka "
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Research platform for fibromyalgia in Japan
Kusuki Nishioka
Arthritis Research & Therapy , 2012, DOI: 10.1186/ar3560
Abstract: FM was initially one the kind for inflammatory muscle pain. Following this concept FM was classified so called soft-tissue rheumatism. Now FM is recognized CNS sensitization following functional pain caused by neuroendocrine system and stress. The abundant neuroendocrine and pain regulation descending pathway and sensitization of pain receptor target molecules such as α2δ ligand, LPA and collapsing response mediator, where currently protein (CRMP) family have been revealed.1990, ACR proposed FM criteria based on 18 tender point sites on digital palpation with exclusive differential diagnosis. In 2010, provisional criteria is score based on total score of severity for pain and somatic symptom (2010 ACR criteria). Based on 2010 ACR criteria, we proposed the assessment of FM severity termed "FAS31". Here, we would like propose the assessment of FM severity score termed FAS31.FDA approved of pregabalin in FM by double-blind, multicenter and randomized study. Both studies enrolled patients with a diagnosis of FM using the ACR criteria. Each of these studies showed a significant reduction in pain compared with placebo. In addition, improvement demonstrated based on FIQ. In Japan, this clinical trial has been developed. Sooner or later, excellent result will be revealed.In other medication, gabapentin practical efficacy for reduced pain with FM patient. Several anti-dispersants (SSTIs, SNRIs. TCAs) NSAIDs, muscle relaxant, anti epileptics and pilocarpine hydrochloride also reduced the pain and an associated symptom. Based on with multivariant statistical analysis based on 3,500 patients, we will present several associated somatic symptoms influencing on drug response for pain and prognosis with FM.In conclusion, FM is one the most important scientific field to understand the pain neurology and rheumatology in near.
Autoimmune response in cartilage-delivered peptides in a patient with osteoarthritis
Kusuki Nishioka
Arthritis Research & Therapy , 2004, DOI: 10.1186/ar1025
Abstract: My colleagues and I have recently reported several lines of evidence for a potential role of immunological intervention in the pathogenic process of osteoarthritis (OA). In particular, we have focused on the role of activated T cells [1] after an immunological response to the cartilage component [2-4] with activation by chemokines [5,6]. The background of this concept comes from a pathological feature of OA synovium. Although OA is generally accepted as one of the commonest degenerative joint disorders caused by biomechanical stress or aging, instances of inflammatory features such as synovial effusion or swelling of affected joints have been reported. The accumulation of mononuclear cells in synovial fluid, an increasing concentration of immunoglobulin and pathological findings of OA synovial tissue such as hyperplasia of synovial lining cells and infiltration of inflammatory cells into the sublining layer strongly suggest chronic inflammatory features of OA. These findings resemble the early stage of rheumatoid arthritis [7-9]. We were therefore interested in the immune response to cartilage components such as cartilage intermediate layer protein (CILP) and YKL39 [10,11]. In particular, endogenous articular cartilage components have been found to provide a rich source of antigenic determinants in OA.We previously detected CD3 T cells in the synovium tissue and CD4+CD8+ cells in the sublining layer in OA. Moreover, the number of interferon-γ-bearing T cells was fivefold that of IL-4-positive cells. In addition, we identified clonal diversity in the infiltrated T cells [1]. These findings of oligoclonal T cell expansion in OA synovium and the presence of T cell aggregates undergoing in situ activation in a rather specific manner indicate that a Th1 cell-mediated specific immune response might be taking place in OA synovium, driven by local antigens.Why should T cells have a potential role in the pathogenic process of cartilage destruction in OA? Current work suggest
p53 in rheumatoid arthritis: friend or foe?
Ulf Müller-Ladner, Kusuki Nishioka
Arthritis Research & Therapy , 2000, DOI: 10.1186/ar84
Abstract: cycle, and apoptotic cell death in rheumatoid arthritis (RA) synovium. In addition, the development of normal synovial fibroblasts into transformed-appearing aggressive synovial fibroblasts may be triggered by the lack of antiproliferative factors, such as p53, p53-associated molecules, other tumor suppressors, as well as by upregulation of anti-apoptotic genes. Therefore, data derived from experiments such as those performed by Tak and colleagues in this issue of Arthritis Research not only enrich the intensive discussion addressing the impact of p53 on RA pathophysiology, they also may facilitate development of novel therapeutic approaches including p53-targeted gene therapy.In this issue of Arthritis Research Tak et al [1] present interesting data on the development of apoptosis and expression of the tumour suppressor gene p53 in adjuvant arthritis (AA). The intention of that study was to evaluate the AA model for its potential to test proapoptotic therapeutic strategies in RA.Because those authors showed that expression of both apoptosis and p53 occurred rather late during the course of the disease, and as levels of p53 were even higher than in RA synovial tissue, the question arises as to whether p53 is the appropriate molecule to target. The tumour suppressor p53, in general, acts by inducing both growth arrest and apoptosis. On the basis of the results of that study [1], and of contributions to our current knowledge of the regulation of apoptosis in RA synovial fibroblasts [2,3,4], p53, when overexpressed early, may ameliorate the course of the disease. Before extrapolating this approach to human RA, however, the actual and/or potential role of p53 in the pathophysiology of RA needs to be discussed and defined. This issue is addressed by the following three questions.For more than a decade, p53 has been one of the most thoroughly examined genes in molecular tumor biology [5,6], which is illustrated by 16597 hits when 'p53' is entered into a PubMed search (htt
Rheumatoid arthritis as a hyper-endoplasmic reticulum-associated degradation disease
Satoshi Yamasaki, Naoko Yagishita, Kaneyuki Tsuchimochi, Kusuki Nishioka, Toshihiro Nakajima
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1808
Abstract: There is a general agreement that synovial cells have a crucial function in rheumatoid arthritis (RA) by forming a mass of synovial tissue, which promotes the production of matrix-degrading proteases and osteoclast activation that lead to joint destruction [1-6]. In a series of experiments that focused on synovial cells, we determined that human T cell leukemia virus type I (HTLV-I) causes arthropathy [7], and that tax, the viral transforming gene of HTLV-1, and its product, pp40Tax, could transform synovial cells of patients as well as those of tax-overexpressing mice [8-10]. These results suggest that synoviocytes can acquire the ability to overgrow autonomously in RA.Here we discuss the role of a novel pathogenic factor for RA named 'Synoviolin' (GenBank accession no. AB024690) [11]. This novel molecule is an endoplasmic reticulum (ER)-resident ubiquitin ligase and is involved in the ER-associated degradation (ERAD) system [12-17]. ERAD is an important processing system for ER homeostasis, and its disruption is known to result in cellular apoptosis [18]. Surprisingly, both the amount and enzymatic activity of Synoviolin regulate synovial cell proliferation and apoptosis, at least in mice [11].We identified Synoviolin from a human cDNA library of rheumatoid synovial cells (RSC) by immunoscreening with anti-RSC antibodies to isolate a molecule promoting the autonomous proliferation and activation of synovial cells in RA [11]. Structurally, Synoviolin has a putative six-transmembrane domain and a RING-H2 motif (Fig. 1). As reported previously, proteins with a RING finger domain act as E3 ubiquitin ligases [19], Synoviolin also exhibits a clear auto-ubiquitination activity [11]. By using immunostaining, we also determined that Synoviolin is located in the ER of synovial cells. We therefore concluded that Synoviolin is an ER-resident E3 ubiquitin ligase [11].Previous studies in yeast and human cells concluded that ER-resident E3 ubiquitin ligases are important for ER
Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases
Seido Ooka, Toshihiro Matsui, Kusuki Nishioka, Tomohiro Kato
Arthritis Research & Therapy , 2003, DOI: 10.1186/ar754
Abstract: Autoantibodies (autoAbs) to cell-surface molecules, including antilymphocyte antibodies, are often detected in the sera of patients with systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although the presence of antilymphocyte antibodies has been correlated with disease activity [1], lymphocyte subset distortions, and functional abnormalities [2,3], the detailed roles of these antibodies remain to be elucidated, as do the roles of autoAbs to surface molecules on other types of cell. One of the main factors hampering the analysis of autoAbs to surface molecules is that only a few target antigens have been identified, such as CD45 [4]. In this regard, we recently reported that CD28, CTLA-4, and CD69 were among the targets of antilymphocyte antibodies [5,6]. In our study on the autoAbs to CD69 [6], most of the tested serum samples recognized only one epitope on CD69. Interestingly, the amino acid sequence of this main epitope (EKNLYWI) is highly homologous to a part (EKRLYWI) of low-density-lipoprotein-receptor-related protein 2 (LRP2). In that study, we showed that autoAbs to the main epitope on CD69 cross-reacted with the homologous epitope in LRP2 [6]. Therefore, the generation of the anti-CD69 autoAbs may be related to that of the anti-LRP2 autoAbs.LRP2 (also designated as megalin or gp330) is one of the superfamily of low-density-lipoprotein receptors (LDLRs) [7,8]. It is a huge molecule, with a molecular weight of approximately 600 kDa, and contains four LDLR domains. LRP2 is expressed in a variety of epithelia, such as renal proximal tubule, epididymis, and thyroid cells. Because mice lacking the gene for LRP2 exhibit a deficiency of proximal tubule reabsorption and a significant reduction of the number and size of organelles associated with endocytosis in the proximal tubule [9], LRP2 is thought to play central roles in reabsorption of proteins and endocytosis. More than 30 ligands for LRP2 have been reported so far, including vitamin-bin
Correction: Catabolic stress induces expression of hypoxia-inducible factor (HIF)-1α in articular chondrocytes: involvement of HIF-1α in the pathogenesis of osteoarthritis
Kazuo Yudoh, Hiroshi Nakamura, Kayo Masuko-Hongo, Tomohiro Kato, Kusuki Nishioka
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1822
Abstract: To examine the role of HIF-1α in the glycosis in human OA chondrocytes, the level of lactic acid was measured in culture chondrocytes by the method reported by Pfander et al. [21]. Supernatants from chondrocyte cultures were collected after 24 hours under normoxic or hypoxic conditions. Lactic acid was determined by a colorimetric assay (Sigma) at 540 nm in accordance with the manufacturer's instructions. Lactic acid levels were normalized to total protein content as measured by the Bradford assay (Bio-Rad, Hercules, CA, USA)To study the role of HIF-1α in energy generation in human OA chondrocytes, the ATP level was analyzed in cultured chondrocytes by the method reported by Pfander et al. [21]. Chondrocytes were collected after a 24-hour incubation under normoxic or hypoxic conditions. The ATP Bioluminescence assay kit CLS II (Roche, Heidelberg, Germany) was used. The assay is based on the light-emitting oxidation of luciferin by luciferase in the presence of extremely low levels of ATP. After collecting the chondrocytes by scraping, cells were centrifuged for 10 min at 500 × g in the cold. Chondrocytes pellets were extracted by boiling 100 mM Tris (tris(hydroxy-methyl)aminomethane) buffer containing 4 mM EDTA (ethylene-diaminetetraacetic acid) for 2 min in order to inactivate NTPases. Cell remnants were removed by centrifugation at 1000 × g. Supernatants were removed and placed on ice. Determination of free ATP was as outlined in the manufacturer's protocol. Light emission was measured at 562 nm using a luminometer. ATP levels were normalized to protein content as measured by the Bradford assay (Bio-Rad) [19].To compare the expression levels of mRNA for HIF-1α we performed real-time PCR according to the method reported by Pfander et al. [21]. For PCR analyses, cDNA from triplicate dishes from four independent experiments (24 hours of hypoxia or normoxia) were diluted to a final concentration of 10 ng/μl. Quantitative real-time RT-PCR was performed with a TaqMan Un
Catabolic stress induces expression of hypoxia-inducible factor (HIF)-1α in articular chondrocytes: involvement of HIF-1α in the pathogenesis of osteoarthritis
Kazuo Yudoh, Hiroshi Nakamura, Kayo Masuko-Hongo, Tomohiro Kato, Kusuki Nishioka
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1765
Abstract: The breakdown or absence of oxygen homeostasis is a hallmark of many common diseases, such as cancer, myocardial infarction, and arthritis. In most normal and tumor tissues, adaptation to hypoxic conditions is critical for successful tissue expansion [1,2]. In response to down-regulation of oxygen homeostasis, cells during hypoxic challenge transiently or chronically tolerate lowered oxygen levels by means of adaptive mechanisms [1]. In mitochondrial oxidative phosphorylation, oxygen is the terminal electron acceptor during ATP production. Several enzymatic reactions require oxygen as a substrate [3,4]. Responses to hypoxia include a metabolic shift to anaerobic glycolysis as well as the initiation of neoangiogenesis via the expression of angiogenic factors to increase the opportunity for oxygen to reach the tissue [1-5]. Oxygen homeostasis and its down-regulation are involved in the pathogenesis of common diseases [3].It is well known that the transcription factor hypoxia-inducible factor 1 (HIF-1) appears to be one of the major regulators of the hypoxic response [3,6]. HIF-1 controls hypoxic expression of erythropoietin, as well as the expression of genes with metabolic functions such as glucose transport and metabolism, and angiogenic factors such as vascular endothelial cell growth factor (VEGF) [6-8]. HIF-1 is a heterodimer of the PAS subfamily of basic-helix-loop-helix transcription factors, and it consists of the subunit HIF-1α (120 kDa), produced in response to hypoxia, and the constitutively expressed HIF-1α (91 to 94 kDa) subunit [9]. HIF-1 protein accumulates and activates the transcription of genes that are of fundamental importance for oxygen homeostasis, including genes involved in energy metabolism, angiogenesis, vasomotor control, apoptosis, proliferation and matrix production, under hypoxic conditions [6,8,9].Articular cartilage is an avascular tissue lacking a capillary network, in which oxygen is limited due to its delivery via diffusion through t
Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function
Kazuo Yudoh, Nguyen van Trieu, Hiroshi Nakamura, Kayo Hongo-Masuko, Tomohiro Kato, Kusuki Nishioka
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1499
Abstract: Articular cartilage matrix undergoes substantial structural, molecular, and mechanical changes with ageing, including surface fibrillation, alteration in proteoglycan structure and composition, increased collagen cross-linking, and decreased tensile strength and stiffness [1,2]. Deterioration in chondrocyte function accompanies these changes in the extracellular matrix [3]. Recently, attention has been given to the suggestion that cartilage ageing and chondrocyte senescence play an important role in the pathogenesis and development of osteoarthritis (OA) [4,5]. Several reports revealed that chondrocyte senescence contributes to the risk for cartilage degeneration by decreasing the ability of chondrocytes to maintain and repair the articular cartilage tissue [4-6]. The mitotic and synthetic activity of chondrocytes decline with advancing donor age [5]. In addition, human chondrocytes become less responsive to anabolic mechanical stimuli with ageing and exhibit an age-related decline in response to growth factors such as the anabolic cytokine insulin-like growth factor-I [6]. These findings provide evidence supporting the concept that chondrocyte senescence may be involved in the progression of cartilage degeneration.Telomeres, the terminal guanine-rich sequences of chromosomes, are structures that function in the stabilization of the chromosome during replication by protecting the chromosome end against exonucleases [7,8]. The telomere DNA may function as a timing mechanism that, when reduced to a critical length, signals a cell to stop dividing and to enter cellular senescence [7-9]. More recent reports demonstrated that the telomere length of chondrocytes shortened with donor ageing and that decreased mean telomere length was closely related to the increase in senescence-associated β-galactosidase expression in human chondrocytes, suggesting that chondrocyte senescence, at least in part, participates in the age-related loss of chondrocyte function responsible for d
Brain perfusion in fibromyalgia patients and its differences between responders and poor responders to gabapentin
Chie Usui, Kotaro Hatta, Nagafumi Doi, Atsushi Nakanishi, Hiroyuki Nakamura, Kusuki Nishioka, Heii Arai
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2980
Abstract: A total of 29 women with fibromyalgia and 10 healthy women (without pain) matched for age were finally enrolled in the study. Technetium-99m ethyl cysteinate dimer single photon emission computed tomography (99mTc-ECD SPECT) was performed in the fibromyalgia patients and controls. A voxel-by-voxel group analysis was performed using Statistic Parametric Mapping 5 (SPM5). After treatment with gabapentin, 16 patients were considered 'responders', with decrease in pain of greater than 50% as evaluated by visual analogue scale (VAS). The remaining 13 patients were considered 'poor responders'.We observed rCBF abnormalities, compared to control subjects, in fibromyalgia including hypoperfusion in the left culmen and hyperperfusion in the right precentral gyrus, right posterior cingulate, right superior occipital gyrus, right cuneus, left inferior parietal lobule, right middle temporal gyrus, left postcentral gyrus, and left superior parietal lobule. Compared to responders, poor responders exhibited hyperperfusion in the right middle temporal gyrus, left middle frontal gyrus, left superior frontal gyrus, right postcentral gyrus, right precuneus, right cingulate, left middle occipital gyrus, and left declive. The right middle temporal gyrus, left superior frontal gyrus, right precuneus, left middle occipital gyrus, and left declive exhibited high positive likelihood ratios.The present study revealed brain regions with significant hyperperfusion associated with the default-mode network, in addition to abnormalities in the sensory dimension of pain processing and affective-attentional areas in fibromyalgia patients. Furthermore, hyperperfusion in these areas was strongly predictive of poor response to gabapentin.Fibromyalgia (FM) is characterized by widespread musculoskeletal chronic pain, fatigue, poor sleep, frequent psychological difficulties, and multiple tender points (TPs) on physical examination [1]. Although neither the etiology nor the pathogenesis of this condition
Sphingosine-1-phosphate attenuates proteoglycan aggrecan expression via production of prostaglandin E2 from human articular chondrocytes
Kayo Masuko, Minako Murata, Hiroshi Nakamura, Kazuo Yudoh, Kusuki Nishioka, Tomohiro Kato
BMC Musculoskeletal Disorders , 2007, DOI: 10.1186/1471-2474-8-29
Abstract: Articular cartilage specimens were obtained from patients with rheumatoid arthritis (RA), osteoarthritis (OA) or traumatic fracture (representing normal chondrocytes) who underwent joint surgery. Isolated HAC were cultured in vitro by monolayer and stimulated with S1P in the presence or absence of inhibitors of signaling molecules. Stimulated cells and culture supernatants were collected and subjected to analyses using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA).All of the tested HAC samples showed positive results in terms of EDG/S1PR expression in basal condition. When HAC was stimulated with S1P, a significant increase in prostaglandin (PG) E2 production was observed together with enhanced expression of cyclooxygenase (COX)-2. S1P stimulated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in HAC, and the PGE2 induction was abrogated by PD98059 and SB203580. Pertussis toxin inhibited the PGE2 induction from HAC by S1P, suggesting an essential role for Gi protein. S1P also attenuated the expression of proteoglycan aggrecan, a component of cartilage matrix, in HAC at transcriptional level.It was suggested that the S1P-induced PGE2 was at least in part involved in the aggrecan-suppressing effect of S1P, seeing as COX inhibitors attenuated the effect. Accordingly, S1P might play an important role in cartilage degradation in arthritides.Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by phosphorylation of sphingosine through activation of sphingosine kinase (reviewed in [1]). S1P exhibits pleiotropic functions, such as cell growth, cell differentiation, survival, angiogenesis, cell migration, and the regulation of immune functions [1,2].Although S1P is released mainly from platelets, other cell types, such as erythrocytes or mononuclear cells, can also produce S1P [3] and high concentrations of S1P can be found in human s
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