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Toshio Matsumoto

Publications and source records attributed to Toshio Matsumoto.

At least 19 recordsLinked to original sources
PubMed2006

Construction of a conventional non-radioisotope method to quantify HM1.24 antigens: correlation of HM1.24 levels and ADCC activity of the humanized antibody against HM1.24.

A humanized monoclonal antibody (mAb) against HM1.24 (AHM) caused antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma (MM) cells. Here, we constructed a conventional non-radioisotope method that quantifies the amount of HM1.24 using fluorescein-labeled AHM. More than 10(4) molecules/cell of HM1.24 were detected in 12 out of 14 patients' MM cells, and a linear correlation was found between ADCC by AHM and the amounts of HM1.24. Thus, AHM is likely to be more efficacious against MM cells with high levels of HM1.24. This conventional non-RI method to quantify HM1.24 will be useful to select patients most likely to respond to AHM.

Antibodies, Monoclonal↗
PubMed2006

Parkin enhances mitochondrial biogenesis in proliferating cells.

We describe a novel function of parkin, a RING protein, which is elaborately involved in mitochondrial biogenesis. Parkin was located within the mitochondrial organelle of proliferating cells. Anti-proliferative treatments released parkin from mitochondria to cytosol. Results of pharmacological treatments indicate that parkin was released from mitochondria when permeability transition pore was opened. The extra-mitochondrial localization was also observed in differentiated cells. In proliferating cells, transcription and replication of mitochondrial DNA was enhanced by parkin overexpression and attenuated by parkin suppression with siRNA. Parkin was associated with mitochondrial transcription factor A (TFAM) and enhanced TFAM-mediated mitochondrial transcription. These results indicate that parkin is involved in the regulation of mitochondrial transcription/replication other than the ubiquitin-mediated protein degradation system in proliferating cells.

Animals↗
PubMed2006

Bone destruction in multiple myeloma.

Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. MM cells enhance bone resorption by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in the bone marrow. Macrophage inflammatory protein (MIP)-1alpha and (MIP)-1beta are secreted by MM cells, and play a major role in the enhancement of bone resorption by MM cells. Furthermore, the growth and survival of MM cells are enhanced by contact with osteoclasts (OCs) suggesting the presence of a vicious cycle between OCs and MM cells. OCs also enhance angiogenesis in concert with MM cells largely through the cooperative actions of osteopontin from OCs and VEGF from MM cells. The angiogenic effect may further facilitate the vicious cycle between bone destruction and MM cell expansion. In addition, MM cells secrete soluble factor(s) to suppress bone formation. Secreted Frizzled-related protein (sFRP)-2, an inhibitor of Wingless type (Wnt) binding to Frizzled, is produced by most MM cells, and immunodepletion of sFRP-2 abrogates the inhibition of bone formation. Thus, MM cells enhance bone resorption and suppress bone formation to cause destructive bone lesions. Further elucidation of the mechanism of bone destruction by MM may lead to a novel therapeutic approach to prevent bone destruction and tumor growth.

Bone Development↗
PubMed2006

Antitumor activity of humanized monoclonal antibody against HM1.24 antigen in human myeloma xenograft models.

A humanized monoclonal antibody against HM1.24 antigen (AHM), which is highly expressed on multiple myeloma (MM) cells, induced antibody-dependent cellular cytotoxicity (ADCC) in vitro. In this study, we further characterized AHM and evaluated its potency for clinical application. AHM bound to HM1.24 antigen with a dissociation constant of 0.35 nM, and its epitope resided between Leu116 and Leu127 of the HM1.24 antigen. Single intravenous injection of AHM significantly inhibited tumor growth in both orthotopic and ectopic human MM xenograft models. AHM reduced serum M protein levels and prolonged survival of mice intravenously inoculated with KPMM2 and ARH-77 cells. The number of KPMM2 cells in bone marrow or tumor volume of subcutaneously inoculated RPMI 8226 cells was also inhibited by AHM. The antitumor activity of AHM against tumor cells in bone marrow was diminished when the mice were pretreated with anti-Fcgamma receptor III/II antibody, demonstrating that antitumor activity by AHM requires effector cell functions in vivo. Experiments involving in vitro ADCC assays indicated that NK cells and monocytes/macrophages serve as effector cells for AHM-induced ADCC in mouse and human. Thus, AHM will provide an additional treatment option for MM.

Animals↗
PubMed2006

[Vitamin D-vitamin D receptor system regulates antithrombogenicity in vivo].

Although it has been well documented that vitamin D receptor (VDR) activation influences the expression of various genes involved in calcium homeostasis and cell differentiation, the physiological role of VDR action in hemostasis remains unclear. We studied thrombogenicity in normocalcemic VDR knock-out (KO) mice on a high calcium diet in comparison with that in wild-type mice and that in hypocalcemic VDRKO mice fed a regular diet. Platelet aggregation was significantly enhanced in normocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretion were reduced in hypocalcemic VDRKO mice but not in normocalcemic VDRKO mice. The gene expression of antithrombin in the liver and that of thrombomodulin in the aorta, liver and kidney were down-regulated in hypo- and normocalcemic VDRKO mice, whereas tissue factor gene expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that the vitamin D-VDR system plays a pivotal role in antithrombogenicity in vivo.

Animals↗
PubMed2005

c-Fos degradation by the ubiquitin-proteasome proteolytic pathway in osteoclast progenitors.

c-Fos is an immediate early gene type proto-oncogene that belongs to the AP (activator protein)-1 transcription factor family. Gene knockout experiments have demonstrated that, among the Fos family, only c-Fos is indispensable for osteoclast differentiation but that c-Fos can be substituted for by other Fos family members including FosB/DeltaFosB, Fra-1 and Fra-2, in most other tissues and cells. To further understand a unique role of c-Fos in osteoclastogenesis, we investigated the temporal profile and regulatory mode of expression of c-Fos during the course of osteoclast differentiation. The results indicated that c-Fos protein gradually increased in preosteoclasts during differentiation to a greater extent than that of mRNA induction. We then determined the proteolytic pathway of c-Fos conferring unstable nature on c-Fos protein in a preosteoclastic cell line, RAW264.7. Proteasome inhibitors including MG132 and Z-LLF caused a rapid increase in c-Fos protein expression in these cells within several hours, but other inhibitors of cysteine protease (E-64), lysosome (chloroquine) and calpain (ALLM) did not. Moreover, the proteasome inhibitors caused an extensive accumulation of ubiquitinated c-Fos protein and an approximately three-fold extension of the c-Fos protein half-life. We therefore conclude that the ubiquitin-proteasome system is the major proteolytic pathway conferring instability on c-Fos protein in preosteoclasts. Our results further imply that c-Fos stabilization due to dynamic changes in the ubiquitin-proteasome-dependent degradation may be involved in the accumulation of c-Fos protein in differentiating preosteoclasts.

Animals↗
PubMed2005

Malignant B-lymphoid cells with bone lesions express receptor activator of nuclear factor-kappaB ligand and vascular endothelial growth factor to enhance osteoclastogenesis.

PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms. EXPERIMENTAL DESIGN AND RESULTS: Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell-derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells. CONCLUSIONS: Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.

Bone Neoplasms↗
PubMed2005

Induction of HM1.24 peptide-specific cytotoxic T lymphocytes by using peripheral-blood stem-cell harvests in patients with multiple myeloma.

HM1.24 antigen is preferentially overexpressed in multiple myeloma (MM) cells but not in normal cells. To explore the potential of HM1.24 as a target for cellular immunotherapy, we selected 4 HM1.24-derived peptides that possess binding motifs for HLA-A2 or HLA-A24 by using 2 computer-based algorithms. The ability of these peptides to generate cytotoxic T lymphocytes (CTLs) was examined in 20 healthy donors and 6 patients with MM by a reverse immunologic approach. Dendritic cells (DCs) were induced from peripheral-blood mononuclear cells of healthy donors or peripheral-blood stem-cell (PBSC) harvests from patients with MM, and autologous CD8(+) T cells were stimulated with HM1.24 peptide-pulsed DCs. Both interferon-gamma-producing and cytotoxic responses were observed after stimulation with either HM1.24-126 or HM1.24-165 peptides in HLA-A2 or HLA-A24 individuals. The peptide-specific recognition of these CTLs was further confirmed by tetramer assay and cold target inhibition assay. Importantly, HM1.24-specific CTLs were also induced from PBSC harvests from patients with MM and these CTLs were able to kill MM cells in an HLA-restricted manner. These results indicate the existence of functional DCs and HM1.24-specific CTL precursors within PBSC harvests and provide the basis for cellular immunotherapy in combination with autologous PBSC transplantation in MM.

Antigens, CD↗
PubMed2005

Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2.

Multiple myeloma (MM) develops devastating bone destruction with enhanced bone resorption and suppressed bone formation. In contrast to enhanced osteoclastogenesis, little is known about the mechanism of impaired bone formation in MM. Because a canonical Wingless-type (Wnt) signaling pathway has recently been shown to play an important role in osteoblast differentiation, we examined whether MM cells affect a canonical Wnt pathway to suppress bone formation. Conditioned media from RPMI8226 and U266 MM cell lines and primary MM cells suppressed in vitro mineralization as well as alkaline phosphatase activity in osteoblasts induced by bone morphogenetic protein 2 (BMP-2). These cell lines constitutively produced a soluble Wnt inhibitor, secreted Frizzled-related protein 2 (sFRP-2), but not other Wnt inhibitors including sFRP-1, sFRP-3, and dickkopf 1 (DKK-1) at the protein level. Most MM cells from patients with advanced bone destructive lesions also expressed sFRP-2. Furthermore, exogenous sFRP-2 suppressed osteoblast differentiation induced by BMP-2, and immunodepletion of sFRP-2 significantly restored mineralized nodule formation in vitro, suggesting a predominant role for MM cell-derived sFRP-2 in the impairment of bone formation by MM. Thus, in addition to enhanced osteolysis, MM cells also suppress bone formation at least in part through an inhibition of the canonical Wnt pathway by secreting sFRP-2.

Animals↗
PubMed2005

Delayed motor and sensory neuropathy in a patient with brainstem encephalitis.

Bickerstaff's brainstem encephalitis (BBE), Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) are thought to be closely related and to form a continuous spectrum. However, chronic polyneuropathy in BBE has not been reported. We report the temporal profile of anti-ganglioside antibody titer in a case of BBE-like brainstem encephalitis complicated with chronic polyneuropathy. A 71-year-old Japanese woman presented with drowsiness and cerebellar ataxia in addition to mild weakness in distal limb muscles. Anti-GalNAc-GD1a IgG and anti-GalNAc-GM1b IgG antibodies were positive in her serum. Brain magnetic resonance imaging revealed high-intensity signals in the midbrain, pons, and middle cerebellar peduncles on T2-weighted images. Central nervous system manifestations improved after immunomodulating therapy that included prednisolone, plasmapheresis and intravenous immunoglobulin. Nevertheless, the distal muscle weakness was exacerbated when the anti-GalNAc-GD1a IgG titer was elevated. Nerve conduction study indicated motor and sensory neuropathy which was developed motor dominant axonal damage. These findings suggest that anti-ganglioside antibodies, including anti-GalNAc-GD1a IgG, may be involved in a common autoimmune mechanism in BBE-like brainstem encephalitis and chronic motor dominant axonal neuropathy. However, the fact that the latter manifestation exacerbated after the improvement of former one possibly indicates different thresholds of neurologic symptoms mediated by anti-ganglioside antibodies in the present patient.

Aged↗
PubMed2005

A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial.

CONTEXT: ED-71 has been shown to increase lumbar bone mineral density (BMD) in osteoporotic subjects. However, vitamin D insufficiency might have influenced the effect of ED-71 on BMD. OBJECTIVE: Our objective was to examine whether ED-71 can increase BMD in osteoporotic patients under vitamin D supplementation. DESIGN, SETTING, AND PATIENTS: We conducted a randomized, double-blind, placebo-controlled clinical trial of 219 osteoporotic patients (49-87 yr of age). INTERVENTIONS: Subjects were randomly assigned to receive placebo or 0.5, 0.75, or 1.0 microg/d ED-71 for 12 months. All the subjects received 200 or 400 IU/d vitamin D(3). MAIN OUTCOME MEASURES: We assessed changes in lumbar and hip BMD and bone turnover markers from baseline. RESULTS: Lumbar BMD increased with ED-71 treatment for 12 months (2.2, 2.6, and 3.1% from baseline and 2.9, 3.4, and 3.8% vs. placebo group in subjects receiving 0.5, 0.75, and 1.0 microg ED-71, respectively). Total hip BMD also increased with 0.75 and 1.0 microg ED-71 (-0.8, 0.6, and 0.9% from baseline and 0.1, 1.5, and 1.8% vs. placebo group in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively). Bone formation and resorption markers were suppressed by approximately 20% after 12 months of 0.75 and 1.0 microg ED-71 treatment. Transient hypercalcemia over 2.6 mmol/liter occurred in 7, 5, and 23% of subjects in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively, but none of them developed sustained hypercalcemia. CONCLUSIONS: These results demonstrate that ED-71 treatment at around 0.75 microg/d can effectively and safely increase lumbar and hip BMD in osteoporotic patients with vitamin D supplementation.

Absorptiometry, Photon↗
PubMed2005

Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis.

Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.

Angiotensin II↗
PubMed2005

Involvement of mitochondria in myasthenia gravis complicated with dermatomyositis and rheumatoid arthritis: a case report.

We report a 57-year-old male with myasthenia gravis complicated with dermatomyositis and rheumatoid arthritis without evidence of thymoma. He showed prominent muscle wasting and weakness in the four extremities and trunk in addition to swallowing disturbance. He showed intolerance to exercise on a bicycle ergometer, and muscle biopsy specimens demonstrated ragged-red fibers. An anti-acetylcholine receptor (AChR) antibody was detected in his serum but no anti-mitochondrial M2 component antibody was found. In contrast, results of immunohistochemical study indicated that his serum sample reacted to muscle mitochondria as well as AChR. These results indicate the presence of an unidentified anti-mitochondrial antibody that may be involved in the development of mitochondrial dysfunction in skeletal muscle of the present patient.

Arthritis, Rheumatoid↗
PubMed2005

Aspirin inhibits thrombin action on endothelial cells via up-regulation of aminopeptidase N/CD13 expression.

OBJECTIVE: We hypothesized that aspirin may exhibit its anti-atherosclerotic effects via mechanisms other than cyclooxygenase inhibition in platelets. METHODS AND RESULTS: Using enhanced subtraction hybridization analysis, we found in human umbilical vein endothelial cells (HUVECs) that aspirin up-regulates the expression of aminopeptidase N (APN/CD13) mRNA and its surface protein levels in a dose-dependent manner. Enzymatic activity of APN/CD13 on HUVECs was increased approximately 1.5-fold by 1 mmol L(-1) of aspirin, and treatment with bestatin, an inhibitor for APN/CD13 metalloprotease activity, attenuated the enhanced activities of APN/CD13. Since activated thrombin receptor is reported to be inactivated by APN/CD13 in vitro, protective actions of aspirin on HUVECs by thrombin stimulation were examined, resulting in the suppression of endothelin-1 and reactive oxygen species productions in HUVECs. These inhibitory actions of aspirin were partially abrogated by bestatin. CONCLUSIONS: Aspirin may exert its anti-atherothrombotic effects in part via the inhibition of thrombin action by up-regulating APN/CD13 on endothelial cells.

Aspirin↗
PubMed2005

Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia.

OBJECTIVE: Mesenchymal stem cells (MSC) are pluripotent cells that differentiate into a variety of cells including endothelial cells and vascular smooth muscle cells. Although transplantation of bone marrow-derived mononuclear cells (MNC) has already been applied for the treatment of critical limb ischemia, little information is available regarding comparison of the angiogenic potency between MSC and MNC. Accordingly, we injected equal numbers of MSC or MNC in a rat model of hindlimb ischemia and compared their therapeutic potential. METHODS AND RESULTS: Immediately after creating hindlimb ischemia, rats were randomized to receive MSC transplantation (MSC group), MNC transplantation (MNC group), or vehicle infusion (Control group). Three weeks after transplantation, the laser Doppler perfusion index was significantly higher in the MNC group than in the Control group (0.69+/-0.1 vs. 0.57+/-0.06, P<0.01). Furthermore, there was a marked improvement in blood perfusion in the MSC group (0.81+/-0.08). Capillary density was highest in the MSC group. The number of transplanted cell-derived endothelial cells was higher in the MSC group than in the MNC group. Transplanted cell-derived vascular smooth muscle cells were detected only in the MSC group. In vitro, MSC were more tolerant to apoptotic stimulus (serum starvation and hypoxia) than MNC. CONCLUSIONS: MSC transplantation caused significantly greater improvement in hindlimb ischemia than MNC transplantation. Compared with MNC, MSC survived well under an ischemic environment, and differentiated into not only endothelial cells but also vascular smooth muscle cells. Thus, MSC transplantation may be a new therapeutic strategy for the treatment of severe peripheral vascular disease.

Animals↗
PubMed2005

Central motor conduction in cervical dystonia with cervical spondylotic myelopathy.

OBJECTIVES: It has been known that cervical dystonia develops secondarily to spinal cord injuries as secondary dystonia. However, little is known about the pathophysiological mechanism. PATIENTS AND METHODS: We examined motor and sensory conduction in six patients with symptomatic cervical dystonia by transcranial magnetic stimulation (TMS). All of the patients exhibited unilateral head rotation. They had symptoms corresponding to cervical myelopathy and felt discomfort in the neck, shoulders or arms before involuntary movement occurred. RESULTS: Although the overall central motor conduction time (CMCT) was not different from that of normal controls, contralateral CMCT was significantly delayed compared to ipsilateral CMCT (p<0.05). The results of somatosensory evoked potential study demonstrated that contralateral central conduction time (CCT) was not significantly different from ipsilateral CCT. CONCLUSION: These findings indicate that there is a selective interference with the contralateral corticospinal tract in patients with symptomatic cervical dystonia.

Adult↗