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1.
Bone ; 95: 1-4, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27989648

RESUMEN

Osteoporosis is characterized as a metabolic disorder of bone tissue, and various metabolic markers are now available to support its diagnosis and evaluate treatment effects. Substances produced as end products of metabolomic activities are the correlated factors to the biological or metabolic status, and thus, metabolites are considered highly sensitive markers of particular pathological states, including osteoporosis. Here we undertook comprehensive serum metabolomics analysis in postmenopausal women with or without low bone mineral density (low BMD vs controls) for the first time using capillary electrophoresis/mass spectrometry. Among the metabolites tested, 57 were detected in sera. Levels of hydroxyproline, Gly-Gly and cystine, differed significantly between groups, with Gly-Gly and cystine significantly lower in the low BMD group and hydroxyproline, a reported marker of osteoporosis, significantly higher. Levels of TRACP5b, a bone resorption marker, were significantly higher in the low BMD group, supporting the study's validity. Taken together, our findings represent novel metabolomic profiling in low BMD in postmenopausal women.


Asunto(s)
Densidad Ósea , Metabolómica , Posmenopausia/sangre , Posmenopausia/fisiología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Metaboloma , Persona de Mediana Edad
2.
Kansenshogaku Zasshi ; 90(3): 316-20, 2016 May.
Artículo en Japonés | MEDLINE | ID: mdl-27529967

RESUMEN

An 84-year-old man was admitted to our hospital with bloody sputum. He was found to have a right lower lobe wedge-shaped nodular lesion with chest X-ray and computed tomography of the chest. Ceftriaxone and minocycline were started empirically based on a working diagnosis of community-acquired pneumonia. Streptococcus parasanguinis was isolated with sputum cultures obtained on three consecutive days and was identified based on its biochemical properties. S. parasanguinis is a member of the sanguinis group of viridans Streptococci. It is known as a causative pathogen for endocarditis. There are very few reports of S. parasanguinis associated with pulmonary infections. The present report describes the association of S. parasanguinis with a wedge-shaped nodular lesion in the lungs.


Asunto(s)
Antibacterianos/uso terapéutico , Ceftriaxona/uso terapéutico , Neumonía/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus/aislamiento & purificación , Anciano de 80 o más Años , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/patología , Humanos , Masculino , Neumonía/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Infecciones Estreptocócicas/patología
3.
Keio J Med ; 65(2): 33-8, 2016 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-26853879

RESUMEN

Low serum 25-hydroxyvitamin D (25(OH)D) levels are implicated as a risk factor for hip and spine fractures. Studies of the relation between 25(OH)D levels and fractures have primarily involved elderly osteoporosis patients or patients with fractures; however, the serum 25(OH)D and parathyroid hormone (PTH) status in younger adult populations remains largely unknown. We evaluated serum 25(OH)D and intact PTH levels in 411 women aged 39-64 years who were not receiving medication for osteoporosis or other bone diseases. Serum 25(OH)D levels were positively correlated with age (P = 0.019), whereas intact PTH levels were inversely correlated with 25(OH)D levels (P < 0.001). Thus, low vitamin D levels with high intact PTH levels were more common in younger than in older women. Our data show that serum 25(OH)D insufficiency could be a more serious concern in the younger population than had been previously anticipated. Because serum 25(OH)D insufficiency is reportedly a risk factor for hip and spine fracture, the number of fracture patients could increase in the future, suggesting that we may need to correct the serum vitamin D/intact PTH status to prevent future osteoporosis.


Asunto(s)
Fracturas de Cadera/prevención & control , Osteoporosis/prevención & control , Hormona Paratiroidea/sangre , Fracturas de la Columna Vertebral/prevención & control , Deficiencia de Vitamina D/diagnóstico , Vitamina D/análogos & derivados , Adulto , Factores de Edad , Femenino , Humanos , Persona de Mediana Edad , Posmenopausia , Premenopausia , Prevención Primaria , Factores de Riesgo , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/fisiopatología
4.
J Biol Chem ; 290(2): 716-26, 2015 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-25404736

RESUMEN

Formation of foreign body giant cells (FBGCs) occurs following implantation of medical devices such as artificial joints and is implicated in implant failure associated with inflammation or microbial infection. Two major macrophage subpopulations, M1 and M2, play different roles in inflammation and wound healing, respectively. Therefore, M1/M2 polarization is crucial for the development of various inflammation-related diseases. Here, we show that FBGCs do not resorb bone but rather express M2 macrophage-like wound healing and inflammation-terminating molecules in vitro. We also found that FBGC formation was significantly inhibited by inflammatory cytokines or infection mimetics in vitro. Interleukin-1 receptor-associated kinase-4 (IRAK4) deficiency did not alter osteoclast formation in vitro, and IRAK4-deficient mice showed normal bone mineral density in vivo. However, IRAK4-deficient mice were protected from excessive osteoclastogenesis induced by IL-1ß in vitro or by LPS, an infection mimetic of Gram-negative bacteria, in vivo. Furthermore, IRAK4 deficiency restored FBGC formation and expression of M2 macrophage markers inhibited by inflammatory cytokines in vitro or by LPS in vivo. Our results demonstrate that osteoclasts and FBGCs are reciprocally regulated and identify IRAK4 as a potential therapeutic target to inhibit stimulated osteoclastogenesis and rescue inhibited FBGC formation under inflammatory and infectious conditions without altering physiological bone resorption.


Asunto(s)
Diferenciación Celular/genética , Células Gigantes de Cuerpo Extraño/metabolismo , Inflamación/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/genética , Animales , Resorción Ósea/genética , Resorción Ósea/metabolismo , Regulación del Desarrollo de la Expresión Génica , Inflamación/patología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Macrófagos/metabolismo , Ratones , Osteoclastos/metabolismo , Osteólisis/genética , Osteólisis/patología
5.
J Biol Chem ; 287(39): 32479-84, 2012 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-22865856

RESUMEN

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.


Asunto(s)
Células Gigantes de Cuerpo Extraño/metabolismo , Proteínas de la Membrana/biosíntesis , Proteínas del Tejido Nervioso/biosíntesis , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT6/metabolismo , Transducción de Señal/fisiología , Animales , Fusión Celular , Regulación de la Expresión Génica/fisiología , Células Gigantes de Cuerpo Extraño/citología , Interleucina-4/genética , Interleucina-4/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT6/genética
6.
J Biol Chem ; 287(34): 28508-17, 2012 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-22761448

RESUMEN

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.


Asunto(s)
Resorción Ósea/metabolismo , Huesos/metabolismo , Diferenciación Celular/fisiología , Osteoclastos/metabolismo , Factores de Transcripción/metabolismo , Animales , Resorción Ósea/genética , Huesos/inmunología , Femenino , Masculino , Ratones , Ratones Transgénicos , Tamaño de los Órganos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción/genética , Factores de Transcripción/inmunología
7.
Biochem Biophys Res Commun ; 421(4): 785-9, 2012 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-22554514

RESUMEN

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 (TGFß) 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.


Asunto(s)
Huesos/citología , Movimiento Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-sis/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Animales , Becaplermina , Movimiento Celular/fisiología , Proliferación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/fisiología , Ratones , Osteoblastos/citología , Osteoblastos/enzimología
8.
J Bone Miner Res ; 27(9): 2015-23, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22508505

RESUMEN

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.


Asunto(s)
Acetaldehído/metabolismo , Aldehído Deshidrogenasa/genética , Mutación/genética , Osteoblastos/patología , Osteogénesis/genética , Osteoporosis/genética , Acetaldehído/farmacología , Adipogénesis/efectos de los fármacos , Aldehído Deshidrogenasa Mitocondrial , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Ratones , Ratones Transgénicos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoporosis/enzimología , Osteoporosis/patología , Fenotipo , Estrés Fisiológico/efectos de los fármacos
9.
J Bone Miner Res ; 27(6): 1289-97, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22337159

RESUMEN

Cell­cell 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-STAMP­deficient mice exhibited a complete lack of cell­cell 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-STAMP­overexpressing transgenic mice with OC-STAMP­deficient mice restored inhibited osteoclast and FBGC cell­cell fusion seen in OC-STAMP­deficient mice. Thus, fusogenic mechanisms in macrophage-lineage cells are regulated via OC-STAMP and DC-STAMP.


Asunto(s)
Células Gigantes de Cuerpo Extraño/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Osteoclastos/metabolismo , Animales , Fusión Celular , Cruzamientos Genéticos , Femenino , Células Gigantes de Cuerpo Extraño/citología , Masculino , Proteínas de la Membrana/deficiencia , Ratones , Ratones Transgénicos , Factores de Transcripción NFATC/metabolismo , Osteoclastos/citología , Osteoclastos/ultraestructura , Unión Proteica
10.
J Exp Med ; 208(11): 2175-81, 2011 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-22006978

RESUMEN

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.


Asunto(s)
Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/fisiología , Osteoclastos/fisiología , Alendronato/farmacología , Animales , Conservadores de la Densidad Ósea/farmacología , Médula Ósea/metabolismo , Células Cultivadas , Factor Estimulante de Colonias de Granulocitos/metabolismo , Células Madre Hematopoyéticas/citología , Ratones , Ratones Transgénicos , Osteoclastos/citología , Osteoclastos/efectos de los fármacos , Osteopetrosis/patología , Osteopetrosis/fisiopatología , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Nicho de Células Madre
11.
J Exp Med ; 207(4): 751-62, 2010 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-20368579

RESUMEN

Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets 'osteoclastic' molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1-Bcl6-osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.


Asunto(s)
Remodelación Ósea/fisiología , Diferenciación Celular/fisiología , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/fisiología , Osteoclastos/citología , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo , Fosfatasa Ácida/metabolismo , Animales , Resorción Ósea/genética , Resorción Ósea/patología , Huesos/citología , Huesos/patología , Catepsina K/genética , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Proteínas de Unión al ADN/genética , Regulación hacia Abajo/genética , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Placa de Crecimiento/patología , Isoenzimas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Proteínas del Tejido Nervioso/genética , Osteoblastos/patología , Osteoclastos/metabolismo , Osteoclastos/patología , Osteopetrosis/genética , Osteopetrosis/patología , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Ligando RANK/farmacología , Transducción de Señal/efectos de los fármacos , Fosfatasa Ácida Tartratorresistente , Factores de Transcripción/genética
12.
Biochem Biophys Res Commun ; 383(3): 373-7, 2009 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-19364494

RESUMEN

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays a critical role in the recruitment and activation of leukocytes. Here, we describe that multinuclear osteoclast formation was significantly inhibited in cells derived from MCP-1-deficient mice. MCP-1 has been implicated in the regulation of osteoclast cell-cell fusion; however defects of multinuclear osteoclast formation in the cells from mice deficient in DC-STAMP, a seven transmembrane receptor essential for osteoclast cell-cell fusion, was not rescued by recombinant MCP-1. The lack of MCP-1 in osteoclasts resulted in a down-regulation of DC-STAMP, NFATc1, and cathepsin K, all of which were highly expressed in normal osteoclasts, suggesting that osteoclast differentiation was inhibited in MCP-1-deficient cells. MCP-1 alone did not induce osteoclastogenesis, however, the inhibition of osteoclastogenesis in MCP-1-deficient cells was restored by addition of recombinant MCP-1, indicating that osteoclastogenesis was regulated in an autocrine/paracrine manner by MCP-1 under the stimulation of RANKL in osteoclasts.


Asunto(s)
Diferenciación Celular , Quimiocina CCL2/metabolismo , Osteoclastos/fisiología , Animales , Comunicación Autocrina , Diferenciación Celular/genética , Fusión Celular , Quimiocina CCL2/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Osteoclastos/metabolismo , Ligando RANK/metabolismo
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