Miki Kondo

Kanazawa Medical University, Kanazawa, Ishikawa, Japan

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Publications (9)38.87 Total impact

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    ABSTRACT: Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM) and are understood to develop under the influence of fibrogenic growth factors. To better understand the detailed mechanisms of persistent fibrosis in SSc, we have previously established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, transforming growth factor-beta (TGF-beta) transiently induced subcutaneous fibrosis and serial injections of connective tissue growth factor (CTGF) after TGF-beta caused persistent fibrosis. These results suggest that CTGF plays an important role in the development of persistent skin fibrosis and that CTGF may be a potential and specific therapeutic target in skin fibrosis. Therefore, the aim of the current study is to develop a neutralizing monoclonal antibody against human CTGF. We also investigated the neutralizing effect of the antibodies in our animal model. Firstly, by using the DNA immunization method, we developed a panel of anti-CTGF antibodies recognizing the native conformation of human CTGF. Next, to examine the anti-fibrosing effects of these antibodies, newborn B6 mice received subcutaneous injections of TGF-beta for 3 days with either anti-CTGF neutralizing antibodies or control purified immunoglobulin. Anti-CTGF antibodies significantly reduced skin fibrosis and collagen contents compared with the control group. These results suggest that our anti-CTGF antibodies are capable of blocking the development of skin fibrosis at least partially and these anti-CTGF neutralizing antibodies may be useful as the feasible strategy to treat skin fibrotic diseases as SSc.
    Journal of Cellular Physiology 10/2008; 216(3):680-7. · 4.22 Impact Factor
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    ABSTRACT: To determine the prevalence of antibodies to individual histone components in collagen disease patients with anti-U1RNP antibodies. Serum samples were examined by enzyme-linked immunosorbent assay. Patients with mixed connective tissue disease (MCTD) and systemic sclerosis (SSc) showed similar levels and patterns of antihistone antibody (AHA) reactivities to individual histones: IgG responses to H2B or H3 and IgM responses to H2B were highest. However, both IgG and IgM AHAs against outer portion of chromatin (H1, H2A, or H2B) were generally higher in SLE compared with other diseases. SLE or SSc patients with anti-U1RNP antibodies showed generally higher AHA levels than in those without them. Thus, the pattern of reactivities to each histone component was dependent on the disease, while the intensity was dependent on both the disease and anti-U1RNP antibodies. The antigenic stimulus in SLE may be different from other connective tissue diseases and is more likely to be native chromatin.
    Rheumatology International 01/2008; 28(2):113-9. · 2.21 Impact Factor
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    ABSTRACT: To investigate the distribution of anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies among patients with autoimmune diseases, and to analyze the clinical features of patients with dermatomyositis (DM) with anti-ARS antibodies. Serum samples from 315 patients with autoimmune diseases or related disorders who had visited Kanazawa University Hospital or affiliated facilities were assessed for anti-ARS antibodies by immunoprecipitation. In particular, the association between anti-ARS antibodies and clinical features was investigated in detail in patients with DM. Anti-ARS antibody was positive in 16 (29%) of 55 patients with DM, 2 (22%) of 9 patients with polymyositis, and 7 (25%) of 28 patients with idiopathic pulmonary fibrosis. Although anti-ARS antibody was detected with high frequency (63%, 15/24) in DM patients with interstitital lung disease (ILD), the incidence of anti-ARS antibody was very low (3%, 1/31) in DM patients without ILD. Anti-ARS antibody-positive patients with DM had significantly higher incidences of ILD (94% vs 23%) and fever (64% vs 10%) than the antibody-negative patients. Some immunosuppressive agents, in addition to oral corticosteroids, were required more frequently in the antibody-positive patients with DM than the antibody-negative patients (88% vs 26%). Although 60% of DM patients with ILD simultaneously developed ILD and myositis, ILD preceded myositis in 33% of patients. Among patients with DM, anti-ARS antibodies are found in a subset with ILD. DM patients with anti-ARS antibodies appear to have a more persistent disease course that requires additional therapy compared to those without anti-ARS antibodies.
    The Journal of Rheumatology 06/2007; 34(5):1012-8. · 3.26 Impact Factor
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    ABSTRACT: To determine the efficacy of self-administered stretching of each finger in Japanese patients with systemic sclerosis (SSc). Forty-five patients with SSc (32 with diffuse cutaneous SSc and 13 with limited cutaneous SSc) were given instructions on self-administered stretching and were directed to perform it every day. Individual fingers were maintained in a stretched position using the opposite hand for 10 seconds and this was repeated 3-10 times. To evaluate the effect of the stretching program, finger passive range of motion (ROM) was assessed using a goniometer on the first visit and after 1 month and 1 year of the stretching program. The Health Assessment Questionnaire (HAQ) was also assessed on the first visit and 1 year afterward. The total passive ROM was significantly improved in each finger after 1 month of finger stretching. The total passive ROM was further improved or maintained within 1 year after the first visit. Although ROM was less in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc at the first visit, ROM increased significantly irrespective of disease duration or severity of skin sclerosis. Finger stretching may improve the finger function, since the HAQ score for hand functions such as eating and gripping was significantly decreased. Our original self-administered stretching program may be useful for improving finger joint motion in patients with SSc; future studies in various ethnic populations will be needed to determine the universal efficacy of this method.
    The Journal of Rheumatology 09/2006; 33(8):1586-92. · 3.26 Impact Factor
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    ABSTRACT: We have encountered a 68-year-old Japanese woman with limited cutaneous systemic sclerosis who developed de novo onset of accelerated hypertension and renal dysfunction; thus we diagnosed scleroderma renal crisis. Anticentromere antibody alone was identified, and not anti-DNA topoisomerase I antibody, anti-RNA polymerase antibodies, anti-Th/To antibodies, or antiribonucleoprotein antibodies, even with use of immunoprecipitation assay. She was successfully treated with angiotensin-converting enzyme inhibitor. This case, scleroderma renal crisis with detection of anticentromere antibody, is thought to be extremely uncommon.
    Modern Rheumatology 02/2006; 16(5):309-11. · 1.72 Impact Factor
  • Journal of Dermatological Science 01/2006; 40(3):215-7. · 3.52 Impact Factor
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    ABSTRACT: c-Ski inhibits transforming growth factor-beta (TGF-beta) signaling through interaction with Smad proteins. c-Ski represses Smad-mediated transcriptional activation, probably through its action as a transcriptional co-repressor. c-Ski also inhibits TGF-beta-induced downregulation of genes such as c-myc. However, mechanisms for transcriptional regulation of target genes by c-Ski have not been fully determined. In this study, we examined how c-Ski inhibits both TGF-beta-induced transcriptional activation and repression. DNA-affinity precipitation analysis revealed that c-Ski enhances the binding of Smad2 and 4, and to a lesser extent Smad3, to both CAGA and TGF-beta1 inhibitory element probes. A c-Ski mutant, which is unable to interact with Smad4, failed to enhance the binding of Smad complex on these probes and to inhibit the Smad-responsive promoter. These results suggest that stabilization of inactive Smad complexes on DNA is a critical event in c-Ski-mediated inhibition of TGF-beta signaling.
    Oncogene 07/2004; 23(29):5068-76. · 8.56 Impact Factor
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    ABSTRACT: A missense mutant of Smad2, Smad2D450E, that was not phosphorylated by transforming growth factor beta (TGF-beta) signaling, was identified in colorectal cancer. Previously, we constructed a mutant Smad3, Smad3D407E, which has an Asp to Glu mutation in the corresponding position of Smad2D450. Smad3D407E was not phosphorylated by the constitutively active form of the TGF-beta type I receptor, and inhibited the phosphorylation of co-expressed wild-type Smad2 and Smad3. In the present study, we examined the inhibitory effects of Smad2D450E on TGF-beta signaling and found that there are considerable differences between Smad2D450E and Smad3D407E. Smad2D450E suppressed the phosphorylation of Smad2, but did not affect the phosphorylation of Smad3, while Smad3D407E blocked the phosphorylation of both Smad2 and Smad3. Consistent with these results, Smad2D450E reduced hetero-oligomer formation of Smad2 with Smad4, but not of Smad3 with Smad4, while Smad3D407E reduced hetero-oligomer formation of both Smad2 and Smad3 with Smad4. However, Smad2D450E reduced the binding of Smad3 to a target DNA element as well as Smad2-binding, and Smad2D450E had inhibitory effects on the transcriptional activity of several targets, as Smad3D407E did. These results suggested that Smad2D450E might block the Smad3-mediated TGF-beta signaling in a hitherto unknown manner after the phosphorylation and hetero-oligomer formation, such as in the process of nuclear translocation or transcriptional regulation, which we could not identify previously by using Smad3D407E.
    Cancer Science 02/2004; 95(1):12-7. · 3.48 Impact Factor
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    ABSTRACT: Transforming growth factor-beta (TGF-beta) has growth-stimulating effects on mesenchymal cells and several tumor cell lines. The signaling pathway for this effect is, however, not well understood. We examined how TGF-beta stimulates proliferation of MG63 human osteosarcoma cells. Two distinct type I receptors for TGF-beta, ALK-1 and ALK-5, were expressed and functional in MG63 cells. Of these two receptors, ALK-5 appears to be responsible for the growth stimulation because expression of constitutively active ALK-5, but not ALK-1, stimulated proliferation of MG63 cells. SB-431542 (0.3 microM), a novel inhibitor of ALK4/5/7 kinase, suppressed TGF-beta-induced growth stimulation. DNA microarray analysis as well as quantitative real-time PCR analysis of RNAs from TGF-beta-treated cells demonstrated that several growth factors, including platelet-derived growth factor AA, were induced in response to TGF-beta in MG63 cells. Gleevec (1 microM) as well as AG1296 (5 microM) inhibited TGF-beta-induced growth stimulation of MG63 cells, suggesting that platelet-derived growth factor AA was mainly responsible for the growth-stimulatory effect of TGF-beta. We also examined the mechanisms of perturbation of growth-suppressing signaling in MG63 cells. We found that expression of c-Myc, which is down-regulated by TGF-beta in many other cells, was up-regulated in MG63 cells, suggesting that up-regulation of c-Myc expression may be the mechanism canceling growth-suppressing signaling of TGF-beta in MG63 cells.
    Cancer Research 12/2003; 63(22):7791-8. · 8.65 Impact Factor