Publications (54)364.69 Total impact
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Article: Twist2 functions as a tumor suppressor in murine osteosarcoma cells.
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ABSTRACT: The epithelial-mesenchymal transition (EMT) contributes to the malignant progression of cancer cells including acquisition of the ability to undergo metastasis. However, whereas EMT-related transcription factors (EMT-TFs) are known to play an important role in the malignant progression of epithelial tumors, their role in mesenchymal tumors remains largely unknown. We have now shown that expression of the gene for Twist2 is down-regulated in human osteosarcoma and correlates inversely with tumorigenic potential in mouse osteosarcoma. Forced expression of Twist2 in highly tumorigenic murine osteosarcoma cells induced a slight inhibition of cell growth in vitro but markedly suppressed tumor formation in vivo. Conversely, knockdown of Twist2 in osteosarcoma cells with a low tumorigenic potential promoted tumor formation in vivo, suggesting that Twist2 functions as a tumor suppressor in osteosarcoma cells. Furthermore, Twist2 induced expression of Fibulin-5, which has been reported as a tumor suppressor. Indeed, medium conditioned by mouse osteosarcoma cells overexpressing Twist2 inhibited expression of the MMP9 gene as well as invasion in mouse embryonic fibroblasts, and forced expression of Twist2 in osteosarcoma cells suppressed MMP9 gene expression in tumor tissue. Our data suggest that Twist2 inhibits formation of a microenvironment conducive to tumor growth and thereby attenuates tumorigenesis in osteosarcoma.Cancer Science 04/2013; · 3.33 Impact Factor -
Article: [Osteoporosis].
Nippon rinsho. Japanese journal of clinical medicine 11/2012; 70 Suppl 8:623-7. -
Article: An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion.
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ABSTRACT: Macrophage lineage cells such as osteoclasts and foreign body giant cells (FBGCs) form multinuclear cells by cell-cell fusion of mononuclear cells. Recently, we reported that two seven-transmembrane molecules, osteoclast stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP), were essential for osteoclast and FBGC cell-cell fusion in vivo and in vitro. However, signaling required to regulate FBGC fusion remained largely unknown. Here, we show that signal transducer and activator of transcription 1 (STAT1) deficiency in macrophages enhanced cell-cell fusion and elevated DC-STAMP expression in FBGCs. By contrast, lack of STAT6 increased STAT1 activation, significantly inhibiting cell-cell fusion and decreasing OC-STAMP and DC-STAMP expression in IL-4-induced FBGCs. Furthermore, either STAT1 loss or co-expression of OC-STAMP/DC-STAMP was sufficient to induce cell-cell fusion of FBGCs without IL-4. We conclude that the STAT6-STAT1 axis regulates OC-STAMP and DC-STAMP expression and governs fusogenic mechanisms in FBGCs.Journal of Biological Chemistry 08/2012; 287(39):32479-84. · 4.77 Impact Factor -
Article: Conditional inactivation of Blimp1 in adult mice promotes increased bone mass.
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ABSTRACT: Bone resorption, which is regulated by osteoclasts, is excessively activated in bone destructive diseases such as osteoporosis. Thus, controlling osteoclasts would be an effective strategy to prevent pathological bone loss. Although several transcription factors that regulate osteoclast differentiation and function could serve as molecular targets to inhibit osteoclast formation, those factors have not yet been characterized using a loss of function approach in adults. Here we report such a study showing that inactivation of B-lymphocyte induced maturation protein 1 (Blimp1) in adult mice increases bone mass by suppressing osteoclast formation. Using an ex vivo assay, we show that osteoclast differentiation is significantly inhibited by Blimp1 inactivation at an early stage of osteoclastogenesis. Conditional inactivation of Blimp1 inhibited osteoclast formation and increased bone mass in both male and female adult mice. Bone resorption parameters were significantly reduced by Blimp1 inactivation in vivo. Blimp1 reportedly regulates immune cell differentiation and function, but we detected no immune cell failure following Blimp1 inactivation. These data suggest that Blimp1 is a potential target to promote increased bone mass and prevent osteoclastogenesis.Journal of Biological Chemistry 07/2012; 287(34):28508-17. · 4.77 Impact Factor -
Article: Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha.
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ABSTRACT: The present study assessed the potential functions of interleukin (IL)-32α on inflammatory arthritis and endotoxin shock models using IL-32α transgenic (Tg) mice. The potential signaling pathway for the IL-32-tumor necrosis factor (TNF)α axis was analyzed in vitro. IL-32α Tg mice were generated under control of a ubiquitous promoter. Two disease models were used to examine in vivo effects of overexpressed IL-32α: Toll-like receptor (TLR) ligand-induced arthritis developed using a single injection of lipopolysaccharide (LPS) or zymosan into the knee joints; and endotoxin shock induced with intraperitoneal injection of LPS and D-galactosamine. TNFα antagonist etanercept was administered simultaneously with LPS in some mice. Using RAW264.7 cells, in vitro effects of exogenous IL-32α on TNFα, IL-6 or macrophage inflammatory protein 2 (MIP-2) production were assessed with or without inhibitors for nuclear factor kappa B (NFκB) or mitogen-activated protein kinase (MAPK). Single injection of LPS, but not zymosan, resulted in development of severe synovitis with substantial articular cartilage degradation in knees of the Tg mice. The expression of TNFα mRNA in inflamed synovia was highly upregulated in the LPS-injected Tg mice. Moreover, the Tg mice were more susceptive to endotoxin-induced lethality than the wild-type control mice 48 hours after LPS challenge; but blockade of TNFα by etanercept protected from endotoxin lethality. In cultured bone marrow cells derived from the Tg mice, overexpressed IL-32α accelerated production of TNFα upon stimulation with LPS. Of note, exogenously added IL-32α alone stimulated RAW264.7 cells to express TNFα, IL-6, and MIP-2 mRNAs. Particularly, IL-32α -induced TNFα, but not IL-6 or MIP-2, was inhibited by dehydroxymethylepoxyquinomicin (DHMEQ) and U0126, which are specific inhibitors of nuclear factor kappa B (NFκB) and extracellular signal regulated kinase1/2 (ERK1/2), respectively. These results show that IL-32α contributed to the development of inflammatory arthritis and endotoxin lethality. Stimulation of TLR signaling with LPS appeared indispensable for activating the IL-32α-TNFα axis in vivo. However, IL-32α alone induced TNFα production in RAW264.7 cells through phosphorylation of inhibitor kappa B (IκB) and ERK1/2 MAPK. Further studies on the potential involvement of IL-32α-TNFα axis will be beneficial in better understanding the pathology of autoimmune-related arthritis and infectious immunity.Arthritis research & therapy 05/2012; 14(3):R120. · 4.27 Impact Factor -
Article: PDGFBB promotes PDGFRα-positive cell migration into artificial bone in vivo.
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ABSTRACT: Bone defects caused by traumatic bone loss or tumor dissection are now treated with auto- or allo-bone graft, and also occasionally by artificial bone transplantation, particularly in the case of large bone defects. However, artificial bones often exhibit poor affinity to host bones followed by bony union failure. Thus therapies combining artificial bones with growth factors have been sought. Here we report that platelet derived growth factor bb (PDGFBB) promotes a significant increase in migration of PDGF receptor α (PDGFRα)-positive mesenchymal stem cells/pre-osteoblastic cells into artificial bone in vivo. Growth factors such as transforming growth factor beta (TGFβ) and hepatocyte growth factor (HGF) reportedly inhibit osteoblast differentiation; however, PDGFBB did not exhibit such inhibitory effects and in fact stimulated osteoblast differentiation in vitro, suggesting that combining artificial bones with PDGFBB treatment could promote host cell migration into artificial bones without inhibiting osteoblastogenesis.Biochemical and Biophysical Research Communications 04/2012; 421(4):785-9. · 2.48 Impact Factor -
Article: Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis.
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ABSTRACT: Osteoporosis is a complex disease with various causes, such as estrogen loss, genetics, and aging. Here we show that a dominant-negative form of aldehyde dehydrogenase 2 (ALDH2) protein, ALDH2*2, which is produced by a single nucleotide polymorphism (rs671), promotes osteoporosis due to impaired osteoblastogenesis. Aldh2 plays a role in alcohol-detoxification by acetaldehyde-detoxification; however, transgenic mice expressing Aldh2*2 (Aldh2*2 Tg) exhibited severe osteoporosis with increased levels of blood acetaldehyde without alcohol consumption, indicating that Aldh2 regulates physiological bone homeostasis. Wild-type osteoblast differentiation was severely inhibited by exogenous acetaldehyde, and osteoblastic markers such as osteocalcin, runx2, and osterix expression, or phosphorylation of Smad1,5,8 induced by bone morphogenetic protein 2 (BMP2) was strongly altered by acetaldehyde. Acetaldehyde treatment also inhibits proliferation and induces apoptosis in osteoblasts. The Aldh2*2 transgene or acetaldehyde treatment induced accumulation of the lipid-oxidant 4-hydroxy-2-nonenal (4HNE) and expression of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that promotes adipogenesis and inhibits osteoblastogenesis. Antioxidant treatment inhibited acetaldehyde-induced proliferation-loss, apoptosis, and PPARγ expression and restored osteoblastogenesis inhibited by acetaldehyde. Treatment with a PPARγ inhibitor also restored acetaldehyde-mediated osteoblastogenesis inhibition. These results provide new insight into regulation of osteoporosis in a subset of individuals with ALDH2*2 and in alcoholic patients and suggest a novel strategy to promote bone formation in such osteopenic diseases.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2012; 27(9):2015-23. · 6.04 Impact Factor -
Article: Vitamin E decreases bone mass by stimulating osteoclast fusion.
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ABSTRACT: Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion. Fat-soluble vitamins such as vitamin D are pivotal in maintaining skeletal integrity. However, the role of vitamin E in bone remodeling is unknown. Here, we show that mice deficient in α-tocopherol transfer protein (Ttpa(-/-) mice), a mouse model of genetic vitamin E deficiency, have high bone mass as a result of a decrease in bone resorption. Cell-based assays indicated that α-tocopherol stimulated osteoclast fusion, independent of its antioxidant capacity, by inducing the expression of dendritic-cell-specific transmembrane protein, an essential molecule for osteoclast fusion, through activation of mitogen-activated protein kinase 14 (p38) and microphthalmia-associated transcription factor, as well as its direct recruitment to the Tm7sf4 (a gene encoding DC-STAMP) promoter. Indeed, the bone abnormality seen in Ttpa(-/-) mice was rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an α-tocopherol-supplemented diet, which contains a comparable amount of α-tocopherol to supplements consumed by many people, lost bone mass. These results show that serum vitamin E is a determinant of bone mass through its regulation of osteoclast fusion.Nature medicine 03/2012; 18(4):589-94. · 27.14 Impact Factor -
Article: Operando QEXAFS studies of Ni₂P during thiophene hydrodesulfurization: direct observation of Ni-S bond formation under reaction conditions.
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ABSTRACT: Structural changes in Ni(2)P/MCM-41 were followed by quick extended X-ray absorption fine structure (QEXAFS) and were directly related to changes in X-ray absorption near-edge structure (XANES) which had been used earlier for the study of the active catalyst phase. An equation is proposed to correct the transient QEXAFS spectra up to second-order in time to remove spectral distortions induced by structural changes occurring during measurements. A good correlation between the corrected QEXAFS and the XANES spectral changes was found, giving support to the conclusions derived from the XANES in the previous work, namely that the formation of a Ni-S bond in a surface NiPS phase is involved in the active site for the hydrodesulfurization reaction.Journal of Synchrotron Radiation 03/2012; 19(Pt 2):205-9. · 2.73 Impact Factor -
Article: Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma.
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ABSTRACT: Osteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal-regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma.Molecular Cancer Research 02/2012; 10(3):454-68. · 4.29 Impact Factor -
Article: Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells.
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ABSTRACT: Cell–cell fusion is a dynamic phenomenon promoting cytoskeletal reorganization and phenotypic changes. To characterize factors essential for fusion of macrophage lineage cells, we identified the multitransmembrane protein, osteoclast stimulatory transmembrane protein (OC-STAMP), and analyzed its function. OC-STAMP–deficient mice exhibited a complete lack of cell–cell fusion of osteoclasts and foreign body giant cells (FBGCs), both of which are macrophage-lineage multinuclear cells, although expression of dendritic cell specific transmembrane protein (DC-STAMP), which is also essential for osteoclast/FBGC fusion, was normal. Crossing OC-STAMP–overexpressing transgenic mice with OC-STAMP–deficient mice restored inhibited osteoclast and FBGC cell–cell fusion seen in OC-STAMP–deficient mice. Thus, fusogenic mechanisms in macrophage-lineage cells are regulated via OC-STAMP and DC-STAMP.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2012; 27(6):1289-97. · 6.04 Impact Factor -
Article: Serum cartilage metabolites as biomarkers of degenerative lumbar scoliosis.
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ABSTRACT: Several biomarkers have been used to evaluate osteoarthritis of the limb joints. Here we evaluated the use of serum cartilage metabolites as biomarkers for degenerative lumbar scoliosis (DLS). Fifty-two DLS patients with Cobb angle > 10° were compared with 19 control patients. Serum levels of hyaluronic acid (HA), keratan sulfate (KS), cartilage oligomeric matrix protein (COMP), collagen type II cleavage (C2C), and procollagen type II C-propeptide (CPII) were measured. Serum levels of KS (DLS 1.20 ± 0.44 µg/ml vs. control 0.98 ± 0.33 µg/ml), CPII (DLS 1905.1 ± 948.2 ng/ml vs. control 1223.6 ± 884.4 ng/ml), and C2C (DLS 219.1 ± 59.2 ng/ml vs. control 177.7 ± 71.7 ng/ml) were significantly higher in DLS. There were no significant differences in the levels of HA or COMP. There was a significant positive correlation between the Cobb angle and CPII in DLS. This is the first study to evaluate the cartilage biomarkers in DLS. The results suggest DLS patients have higher levels of type II collagen synthesis and degradation, indicated by elevated serum CPII and C2C, respectively. As type II collagen is a major component of collagens in the nucleus pulposus and facet joint cartilages, its enhanced turnover may be related to the development and progression of DLS.Journal of Orthopaedic Research 01/2012; 30(8):1249-53. · 2.81 Impact Factor -
Article: Neovascular niche for human myeloma cells in immunodeficient mouse bone.
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ABSTRACT: The interaction with bone marrow (BM) plays a crucial role in pathophysiological features of multiple myeloma (MM), including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model). Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138(+) myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin(+) MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin(-) population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.PLoS ONE 01/2012; 7(2):e30557. · 4.09 Impact Factor -
Article: Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization.
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ABSTRACT: Hematopoietic stem cells (HSCs) are maintained in a specific bone marrow (BM) niche in cavities formed by osteoclasts. Osteoclast-deficient mice are osteopetrotic and exhibit closed BM cavities. Osteoclast activity is inversely correlated with hematopoietic activity; however, how osteoclasts and the BM cavity potentially regulate hematopoiesis is not well understood. To investigate this question, we evaluated hematopoietic activity in three osteopetrotic mouse models: op/op, c-Fos-deficient, and RANKL (receptor activator of nuclear factor kappa B ligand)-deficient mice. We show that, although osteoclasts and, by consequence, BM cavities are absent in these animals, hematopoietic stem and progenitor cell (HSPC) mobilization after granulocyte colony-stimulating factor injection was comparable or even higher in all three lines compared with wild-type mice. In contrast, osteoprotegerin-deficient mice, which have increased numbers of osteoclasts, showed reduced HSPC mobilization. BM-deficient patients and mice reportedly maintain hematopoiesis in extramedullary spaces, such as spleen; however, splenectomized op/op mice did not show reduced HSPC mobilization. Interestingly, we detected an HSC population in osteopetrotic bone of op/op mice, and pharmacological ablation of osteoclasts in wild-type mice did not inhibit, and even increased, HSPC mobilization. These results suggest that osteoclasts are dispensable for HSC mobilization and may function as negative regulators in the hematopoietic system.Journal of Experimental Medicine 10/2011; 208(11):2175-81. · 13.85 Impact Factor -
Article: IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis.
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.International Immunology 09/2011; 23(11):701-12. · 3.41 Impact Factor -
Article: Matrix metalloproteinase 13 in the ligamentum flavum from lumbar spinal canal stenosis patients with and without diabetes mellitus.
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ABSTRACT: Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in the elderly, and ligamentum flavum (LF) hypertrophy is an important cause of LSCS. Matrix metalloproteinase 13 (MMP13) can degrade fibrillar collagens and elastic microfibrils, and is involved in inflammation and fibrosis. The purpose of this study was to compare the expression of MMP13 in the LF from LSCS patients with diabetes mellitus [DM (+)] with that in the LF from patients without DM [DM (-)] and to analyze the relationship among DM, MMP13 expression, and LF hypertrophy. LFs from 11 DM (+) and 24 DM (-) LSCS patients were analyzed in this study. Histology analysis using hematoxylin and eosin and Masson's trichrome stain was performed for each LF. The expression of MMP13 was analyzed by quantitative real-time PCR. The thickness of LF was measured by CT. In the LF from DM (+) LSCS patients, the elastic fibers were more disorganized and had lower volumes than in the LF from DM (-) LSCS patients, while more fibrotic tissue was observed in the LF from DM (+) than from DM (-) LSCS patients. MMP13 expression was significantly higher in the LF from DM (+) LSCS patients (0.46 ± 0.61 vs. 0.05 ± 0.09, P = 0.002). The LF from the DM (+) LSCS patients was significantly thicker than that from the DM (-) LSCS patients (5.0 ± 0.9 vs. 3.1 ± 0.8 mm, P < 0.01), and the thickness was correlated with the expression of MMP13 (correlation coefficient = 0.43, P = 0.01, Pearson's correlation test). DM-related MMP13 expression can be one of the factors contributing to fibrosis and hypertrophy of the LF. Further research on the mechanism of this process may lead to new therapies for LF hypertrophy.Journal of Orthopaedic Science 08/2011; 16(6):785-90. · 0.84 Impact Factor -
Article: [Suppressive effects for osteoclastogenesis regulated by RANKL signal].
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ABSTRACT: RANKL signal promotes osteoclast differentiation through a transcriptional activation of responsible genes for osteoclast formation and functions. Recent works revealed that RANKL signal plays a role to repress transcription of suppressive factors for osteoclastogenesis. Some transcriptional repressors actively inhibit expressions of osteoclast-specific genes in the precursors through canceling the functions of transcription activators to prevent uncontrollable osteoclast formation and pathological bone resorption. The mouse models lacking those transcriptional repressors exhibited accelerated osteoclast differentiation and bone loss. Although the suppressive factors are important for maintaining bone homeostasis, they have to be removed for osteoclast formation in the presence of RANKL. The transcriptional repressor Blimp1 was identified as a new target of RANKL signal and strongly attenuated expressions of various suppressive factors including Bcl6. The osteoclast-specific Blimp1 knockout mice exhibited defect of osteclast formation and loss of bone resorption. Thus, RANKL signal regulates osteoclast differentiation by inducing transcriptional activators such as NFATc1 as well as transcriptional repressors such as Blimp1.The former is essential for expressions of osteclast-specific genes, while the latter is required for terminating suppressions of osteoclast differentiation.Clinical calcium 08/2011; 21(8):1141-7. -
Article: Mechanism of osteoporosis in adolescent idiopathic scoliosis: experimental scoliosis in pinealectomized chickens.
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ABSTRACT: To clarify the mechanism of osteoporosis in adolescent idiopathic scoliosis (AIS), we investigated radiological and histological changes in the cervical vertebrae of a chicken thoracic scoliosis model. Forty newly hatched broiler chicks were randomly divided into four equal groups: sham-operated chickens serving as control (CON), pinealectomized chickens (PNX), sham-operated (CON + MLT) and pinealectomized chickens (PNX + MLT) that received intraperitoneal administration of melatonin. Pinealectomy was performed at the age of 3 days, and the chickens were killed at 2 months of age. Postmortem X-rays were examined for the presence of scoliosis, and micro-computed tomography (micro-CT) images were taken to evaluate the microstructure of the cervical vertebrae. Histological specimens of the scanned cervical vertebra were prepared, and a midsagittal section was stained with hematoxylin and eosin and tartrate-resistant acid phosphatase to evaluate the numbers of osteoblasts and osteoclasts, respectively. Scoliosis developed at the thoracic spine in all chickens of the PNX and in two of the PNX + MLT group. Micro-CT data revealed that chickens in the PNX group had a greater degree of generalized osteoporosis compared with the other birds. The number of osteoblasts was significantly decreased in the PNX group, while no significant difference was observed among chickens in the numbers of osteoclasts. Our results suggest that melatonin deficiency reduces osteoblast proliferation and leads to the development of scoliosis and osteoporosis. The restoration of melatonin prevented the development of scoliosis and osteoporosis, indicating that melatonin levels may be crucial to the development of deformity and osteoporosis in AIS.Journal of Pineal Research 04/2011; 51(4):387-93. · 5.79 Impact Factor -
Chapter: Molecules Regulating Macrophage Fusions
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ABSTRACT: Multinuclear giant cells derived from hematopoietic stem cells or monocyte/macrophage lineage cells are subdivided into osteoclasts, bone resorbing cells, and macrophage giant cells (MGCs) including foreign body giant cells (hereafter described as FBGCs), which are induced at the site of implanted biomaterials, tumors, chronic inflammation and an infection such as tuberculosis. The most characteristic feature of these cells is multinucleation induced by the cell–cell fusion of mononuclear cells, a phenomenon first reported over 60 years ago. To date, combinations of cytokines for osteoclastogenesis or MGC formation have been identified, and osteoclasts and MGCs can be generated in the presence of specific combinations of cytokines in vitro. This makes it possible to isolate specific molecules for cell–cell fusion or to analyze the mechanisms and roles of multinucleation in osteoclasts and MGCs. Recent studies have accumulated data on molecules essential for the cell–cell fusion of osteoclasts and MGCs, and on the role of cell–cell fusion of osteoclasts and MGCs in bone homeostasis and foreign body reactions, respectively. Thus, the role of the cell–cell fusion of osteoclasts in bone homeostasis has been, at least in part, clarified. Furthermore, macrophages reportedly fuse not only with macrophages in a homophilic manner but also with somatic cells and tumors in a heterophilic manner, and the heterophilic fusion is considered involved in tissue repairs and tumor metastasis. Similar to this heterophilic cell–cell fusion, some types of virus such as human immune deficiency virus and influenza virus fuse to somatic cells during an infection. In this chapter, recent advances in the molecular understanding of cell–cell fusion in macrophages will be discussed. KeywordsBone homeostasis-CD9-CD81-cell-cell fusion-cytokines-DC-STAMP-foreign body reactions-giant cells-monocyte-macrophage-osteoclast-phagocytosis-RANK-RANKL11/2010: pages 233-248; -
Article: [Cytokines in bone diseases. Osteoprotegerin and juvenile Paget's disease].
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ABSTRACT: Juvenile Paget's disease (JPD) is a rare autosomal-recessive hereditary disease and is typically diagnosed in infants or young children. JPD causes bone pain, bone expansion and deformity, and severity generally increases during adolescence. Recently, differentiation and maturation of osteoclasts, controlled by RANK, which is expressed in osteoclast precursors and its ligand, RANKL, which is expressed in osteoblasts or marrow stromal cells, have been clarified. Recent studies elucidated that JPD was caused by mutation of TNFRSF11B, which encodes osteoprotegerin, a soluble decoy receptor of RANKL. We summarize the outline and etiology of JPD.Clinical calcium 10/2010; 20(10):1540-4.
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2003–2012
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Keio University
- School of Medicine
Tokyo, Tokyo-to, Japan
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