LIOMM
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El Laboratorio de Investigación en Osteopatías y Metabolismo Mineral fue creado en el año 2012 como una unidad multidisciplinaria dedicada a la investigación científico-tecnológica, con el fin de incrementar los conocimientos científicos, la educación y la extensión en el campo de las patologías óseas y metabólicas, así como su aplicación en la ingeniería de tejidos. Nuestras áreas de interés son: Osteopatías, Metabolismo Mineral, Diabetes mellitus, Síndrome Metabólico, Ingeniería de Tejido. Abordamos aspectos de la fisiopatología del esqueleto, asociadas con enfermedades metabólicas de alta prevalencia como la Diabetes mellitus, Síndrome Metabólico y obesidad. Investigamos las posibles causas de estas osteopatías metabólicas, sus tratamientos con diferentes fármacos, así como terapia celular usando células progenitoras de médula ósea. Para contribuir al espectro terapéutico disponible para las distintas patologías óseo-cartilaginosas, desarrollamos y estudiamos matrices poliméricas que sirvan como sistemas de liberación controlada de drogas, y/o como scaffolds para la reparación del tejido oseo-articular.
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Acceso Abierto Advanced glycation end products and strontium ranelate promote osteogenic differentiation of vascular smooth muscle cells in vitro: preventive role of vitamin D(2017) Molinuevo, María Silvina; Fernández, Juan Manuel; Cortizo, Ana María; McCarthy, Antonio Desmond; Schurman, León; Sedlinsky, ClaudiaAdvanced glycation end products (AGE) have been demonstrated to induce the osteogenic transdifferentiation of vascular smooth muscle cells (VSMC). Strontium ranelate (SR) is an anti-osteoporotic agent that has both anti-catabolic and anabolic actions on bone tissue. However, in the last years SR has been associated with an increase of cardiovascular risk. We hypothesize that SR can increase the osteoblastic trans-differentiation of VSMC and the induction of extracellular calcifications, an effect that could be potentiated in the presence of AGE and inhibited by simultaneous administration of vitamin D. The present results of our in vitro experiments demonstrate that AGE and SR alone or in combination, stimulate L-type calcium channels, causing an increase in reactive oxygen species and activation of both ERK and NFkB, with the final effect of promoting the osteogenic shift of VSMC. Importantly, these in vitro effects of AGE and/or SR can be prevented by co-incubation with vitamin D. - Artículo
Acceso Abierto Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK)(2003) Cortizo, Ana María; Lettieri, M.G.; Barrio, D.A.; Mercer, N.; Etcheverry, S.B.; McCarthy, Antonio DesmondAn increase in the interaction between advanced glycation end-products (AGEs) and their receptor RAGE is believed to contribute to the pathogenesis of chronic complications of Diabetes mellitus, which can include bone alterations such as osteopenia. We have recently found that extracellular AGEs can directly regulate the growth and development of rat osteosarcoma UMR106 cells, and of mouse calvaria-derived MC3T3E1 osteoblasts throughout their successive developmental stages (proliferation, differentiation and mineralisation), possibly by the recognition of AGEs moieties by specific osteoblastic receptors which are present in both cell lines. In the present study we examined the possible expression of RAGE by UMR106 and MC3T3E1 osteoblastic cells, by immunoblot analysis. We also investigated whether short-, medium- or long-term exposure of osteoblasts to extracellular AGEs, could modify their affinity constant and maximal binding for AGEs (by 125I-AGE-BSA binding experiments), their expression of RAGE (by immunoblot analysis) and the activation status of the osteoblastic ERK 1/2 signal transduction mechanism (by immunoblot analysis for ERK and P-ERK). Our results show that both osteoblastic cell lines express readily detectable levels of RAGE. Short-term exposure of phenotypically mature osteoblastic UMR106 cells to AGEs decrease the cellular density of AGE-binding sites while increasing the affinity of these sites for AGEs. This culture condition also dose-dependently increased the expression of RAGE and the activation of ERK. In proliferating MC3T3E1 pre-osteoblasts, 24-72 h exposure to AGEs did not modify expression of RAGE, ERK activation or the cellular density of AGE-binding sites. However, it did change the affinity of these binding sites forAGEs, with both higher- and lower-affinity sites now being apparent. Medium-term ( 1 week) incubation of differentiated MC3T3E1 osteoblasts with AGEs, induced a simultaneous increase in RAGE expression and in the relative amount of P-ERK. Mineralising MC3T3E1 cultures grown for 3 weeks in the presence of extracellular AGEs showed a decrease both in RAGE and P-ERK expression. These results indicate that, in phenotypically mature osteoblastic cells, changes in ERK activation closely follow the AGEs-induced regulation of RAGE expression. Thus, the AGEs-induced biological effects that we have observed previously in osteoblasts, could be mediated by RAGE in the later stages of development, and mediated by other AGE receptors in the earlier pre-osteoblastic stage. - Artículo
Acceso Abierto Advanced Glycation Endproducts and Alendronate Differentially Inhibit early and Late Osteoclastogenesis In vitro(2013) Gangoiti, María Virginia; Arnol, Verónica; Cortizo, Ana María; McCarthy, Antonio DesmondAdvanced Glycation Endproducts (AGEs) are greatly elevated in bone extracellular matrix of patients with Diabetes mellitus, and this has been associated with the increased incidence of fractures observed in these patients. AGEs affect the homeostasis of bone cells such as osteoblasts and osteoclasts. Bisphosphonates are first-line anti-osteoporotic drugs that principally exert their effects by inhibiting osteoclastic activity. However, the effect of bisphosphonate treatment on bone quality in patients with Diabetes is uncertain. In the present work we have evaluated the action of AGEs (50-200 μg/ml), with or without Alendronate (10-8-10-4M), on osteoclastogenesis induced by co-cultures of Raw 264.7 macrophages and UMR106 osteoblasts. We determined the effects of different culture conditions on osteoclastic recruitment, tartrate-resistant acid phosphatase (TRAP) activity and expression of RAGE (receptor for AGEs); and on the osteoblastic expression of RANK ligand (RANKL). AGEs and Alendronate inhibited the recruitment and TRAP activity of osteoclasts, with an additive effect of both agents at high concentrations of Alendronate. While AGEs prevented the early and late stages of osteoclastogenesis, Alendronate (alone or in co-incubation with AGEs) only inhibited its later stages. In addition, both AGEs and Alendronate increased the osteoclastic expression of RAGE and decreased the osteoblastic expression of RANKL, correlating closely with their inhibition of osteoclastogenesis. If these in vitro results can be extrapolated to a clinical setting, they may be indicating a potentiation of the anti-resorptive effects of Alendronate in the context of bone extracellular matrix with excess accumulation of AGEs, as might occur in a patient with Diabetes mellitus. - Artículo
Acceso Abierto Advanced glycation endproducts interfere with integrin-mediated osteoblastic attachment to a type-I collagen matrix(2004) McCarthy, Antonio Desmond; Uemurab, Toshimasa; Etcheverry, Susana B.; Cortizo, Ana MaríaThe adhesion of osteoblasts to bone extracellular matrix, of which type-I collagen constitutes >85%, can modulate diverse aspects of their physiology such as growth, differentiation and mineralisation. In this study we examined the adhesion of UMR106 rat osteoblast-like cells either to a control (Col) or advanced-glycation-endproduct-modified (AGEs-Col) type I collagen matrix. We investigated the possible role of different integrin receptors in osteoblastic adhesion, by co-incubating these cells either with β-peptide (conserved sequence 113–125 of the β subunit of integrins) or with two other peptides, RGD (Arg-Gly-Asp) and DGEA (Asp-Gly-Glu-Ala), which are recognition sequences for the α-subunits of α1,5β1and α2β1integrins. Collagen glycation inhibited the adhesion of UMR106 osteoblasts to the matrix (40% reduction versus Col,P<0.001). β-Peptide showed a dose- and glycation-dependent inhibitory effect on adhesion, and at a concentration of 100μM decreased the attachment of UMR106 cells to both matrices (42% to Col,P<0.001; and 25% to AGEs-Col,P<0.01). The synthetic peptides RGD (1mM) and DGEA (5mM) inhibited the attachment of UMR106 cells to Col (30 and 20%,P<0.01 andP<0.001, respectively), but not to AGEs-Col. β-Peptide induced an increase in UMR106 cell clumping and a decrease in cellular spreading, while DGEA increased spreading with cellular extensions in multiple directions. These results indicate that both α and β integrin subunits participate in osteoblastic attachment to type-I collagen, probably through the α1,5β1and α2β1integrins. AGEs-modification of type-I collagen impairs the integrin-mediated adhesion of osteoblastic cells to the matrix, and could thus contribute to the pathogenesis of diabetic osteopenia. - Artículo
Acceso Abierto AGE-R3/galectin-3 expression in osteoblast-like cells: Regulation by AGEs(2004) Mercer, Natalia; Ahmed, Hafiz; McCarthy, Antonio Desmond; Etcheverry, Susana B.; Vasta, Gerardo R.; Cortizo, Ana MaríaThe accumulation of irreversible advanced glycation endproducts (AGEs) on long-lived proteins, and the interaction of AGEs with cellular receptors such as AGE-R3/galectin-3 and RAGE, are considered to be key events in the development of longterm complications of diabetes mellitus, Alzheimer’s disease, uremia and ageing. The aim of this study was to investigate the expression and sub-cellular distribution of galectin-3, as well as its possible modulation by AGEs, in MC3T3E1 mouse calvaria-derived osteoblasts and in UMR 106 rat osteosarcoma cells. Both osteoblastic lines were cultured either with control bovine serum albumin (BSA) or with AGEs-BSA for 48 h. Cells were evaluated for galectin-3 expression by fixing and immunofluorescent microscopic analysis; or Western blot analysis of whole cell extracts, sub-cellular fractions and culture media. Both cell lines express 30 kDa (monomeric) galectin-3, although expression was about 15-fold lower in the UMR106 osteosarcoma cells. Dimeric (70 kDa) galectin-3 was additionally observed in the UMR106 cells. Immunofluorescent analysis of galectin-3 distribution showed a diffuse cytoplasmic and strong nuclear pattern in MC3T3E1 osteoblasts, and a patchy cytoplasmic pattern in UMR106 cells. Western blot analysis for both cell lines showed that galectin-3 was mainly found in the cytoplasm and in minor amounts in the microsomal fraction, while considerable amounts were secreted into the culture media. Exposure to 100–200 μg/mL AGEs-BSA increased the cellular content of 30 kDa galectin-3 (20–25% for MC3T3E1 and 35–70% for UMR106 versus control BSA, p < 0.05), and decreased the culture media levels of galectin-3 (10–20% for MC3T3E1 and for UMR106 versus control BSA, p < 0.05). These results confirm the expression of galectin-3 in osteoblastic cells, and suggest different levels and sub-cellular distribution of this protein in transformed versus non-transformed osteoblasts. Osteoblastic exposure to AGEs alters their expression and secretion of galectin-3, which could have significant consequences on osteoblast metabolism and thus on bone turnover. - Artículo
Acceso Abierto Alendronate Can Improve Bone Alterations in Experimental Diabetes by Preventing Antiosteogenic, Antichondrogenic, and Proadipocytic Effects of AGEs on Bone Marrow Progenitor Cells(Hindawi Publishing Corporation, 2016) Chuguransky, Sara Rocío; Cortizo, Ana María; McCarthy, Antonio DesmondBisphosphonates such as alendronate are antiosteoporotic drugs that inhibit the activity of bone-resorbing osteoclasts and secondarily promote osteoblastic function. Diabetes increases bone-matrix-associated advanced glycation end products (AGEs) that impair bone marrow progenitor cell (BMPC) osteogenic potential and decrease bone quality. Here we investigated the in vitro effect of alendronate and/or AGEs on the osteoblastogenic, adipogenic, and chondrogenic potential of BMPC isolated from nondiabetic untreated rats. We also evaluated the in vivo effect of alendronate (administered orally to rats with insulindeficient Diabetes) on long-bone microarchitecture and BMPC multilineage potential. In vitro, the osteogenesis (Runx2, alkaline phosphatase, type 1 collagen, and mineralization) and chondrogenesis (glycosaminoglycan production) of BMPC were both decreased by AGEs, while coincubation with alendronate prevented these effects.The adipogenesis of BMPC (PPAR��, intracellular triglycerides, and lipase) was increased by AGEs, and this was prevented by coincubation with alendronate. In vivo, experimental Diabetes (a) decreased femoral trabecular bone area, osteocyte density, and osteoclastic TRAP activity; (b) increased bone marrow adiposity; and (c) deregulated BMPC phenotypic potential (increasing adipogenesis and decreasing osteogenesis and chondrogenesis). Orally administered alendronate prevented all these Diabetes-induced effects on bone. Thus, alendronate could improve bone alterations in diabetic rats by preventing the antiosteogenic, antichondrogenic, and proadipocytic effects of AGEs on BMPC. - Artículo
Acceso Abierto Alendronate induces anti-migratory effects and inhibition of neutral phosphatases in UMR106 osteosarcoma cells(2007) Molinuevo, M.S.; Bruzzone, L.; Cortizo, Ana MaríaBisphosphonates are nonhydrolysable pyrophosphate analogues that prevent bone loss in several types of cancer. However, the mechanisms of anticancer action of bisphosphonates are not completely known. We have previously shown that nitrogen-containing bisphosphonates directly inhibit alkaline phosphatase of UMR106 rat osteosarcoma cells. In this study, we evaluated the effects of alendronate on the migration of UMR106 osteosarcoma using a model of multicellular cell spheroids, as well as the alendronate effect on neutral phosphatases. Alendronate significantly inhibited the migration of osteoblasts in a dose-dependent manner (10(-6)-10(-4) M). This effect was also dependent on calcium availability. The spheroid morphology and distribution of actin fibers were also affected by alendronate treatment. Alendronate dose-dependently inhibited neutral phosphatase activity in cell-free osteoblastic extracts as well as in osteoblasts in culture. Our results show that alendronate inhibits cell migration through mechanisms dependent on calcium, and that seem to involve inhibition of phosphotyrosine-neutral-phosphatases and disassembly of actin stress fibers. - Artículo
Acceso Abierto Biocompatibility and biodegradation of polyester and polyfumarate based-scaffolds for bone tissue engineering(2008) Cortizo, María Susana; Molinuevo, Silvina; Cortizo, Ana MaríaBiodegradable and biocompatible polymeric scaffolds have been recently introduced for tissue regeneration purpose. In the present study we aimed to develop polymeric-based scaffolds for bone regeneration. Two polyesters, poly-β-propiolactone (PBPL), poly-ε-caprolactone (PCPL) and two polyfumarates, polydiisopropyl fumarate (PDIPF), polydicyclohexyl fumarate (PDCF) were chosen to prepare films which can support osteoblastic growth. Scanning electron microscopy and water contact angle were used to characterize the matrices. Biodegradation studies were performed both in PBS buffer and using an in vitro macrophage degradation assay. Mouse calvaria-derived MC3T3E1 cells and UMR106 rat osteosarcoma cell lines were used to perform biocompatibility and cytotoxicity studies. The polyesters, the most hydrophilic polymers studied, showed a rougher and more porous surfaces than the polyfumarates. Under acellular conditions, only PBPL was degraded by hydrolytic mechanisms. However, macrophages performed an active degradation of all polymeric films. Osteoblasts developed well-defined actin fibres without evidence of cytotoxicity when growing on the films. The number of UMR106 osteoblasts that adhered to the PBPL-based film was higher than that of the cells attached to the PECL and polyfumarates (PDIPF and PDCF) matrices. Both UMR106 and MC3T3E1 osteoblastic lines showed protein levels comparable to control conditions, demonstrating that they grew well on all surfaces. However, UMR106 cells showed a significant increase in proliferation on polyester-derived scaffolds (PBPL and PECL). The alkaline phosphatase activity of UMR106, an osteoblastic marker, was significantly higher than that of control plastic dishes. MC3T3E1 cells expressed similar levels of this differentiation marker in all polymeric matrices. We found similar collagen protein content after 48 h culture of UMR106 cells on all surfaces. However, important differences were evident in the MC3T3E1 line. In conclusion, the synthetic polymeric-based scaffold we have developed and studied supports adhesion, growth and differentiation of two osteoblastic cell lines, suggesting that they could be useful in bone tissue regeneration. Copyright 2008 John Wiley & Sons, Ltd. - Documento de conferencia
Acceso Abierto Caracterización y biocompatibilidad de matrices de colágeno para uso en regeneración ósea(2010) Cortizo, Ana María; Ruderman, G.; Mogilner, G.; Tolosa, E.J.El colágeno, la proteína más abundante del hueso, juega un rol fundamental en la integridad biológica y estructural del esqueleto. Previamente se han usado membranas de colageno sin un orden molecular, para fabricar matrices para la regeneración del tejido óseo. El colágeno es así un candidato natural para mejorar o reemplazar tejidos u órganos dañados. El objetivo del presente trabajo es caracterizar matrices de colágeno ordenado o no (con una distribución al azar) y estudiar su biocompatiblidad con células óseas en cultivo. Se estilizó colágeno extraído del tendón de Aquiles bovino, nativo, obtenido en nuestro laboratorio con un grado de pureza de un 98% [Ruderman et al., 2007]. Se fabricaron matrices de colágeno no ordenado y de colágeno ordenado según patentes. Las características de la superficie de membranas fueron observadas por SEM y microscopia óptica (coloración de Sirius red). Las membranas ordenadas mostraron una topografía típica en forma de canales en correlación con un ordenamiento molecular. Se evaluó la biocompatibilidad de células osteoblásticas y macrófagos murinos crecidos sobre los dos tipos de películas de colágeno (No ordenado y ordenado). Se estudió la adhesión, proliferación (conteo de células teñidas con Giemsa) y diferenciación al fenotipo osteoblasto (expresión de fosfatasa alcalina y nódulos de mineralización). Se encontró que las células (osteoblasticas y macrófagos) crecidas sobre las matrices de colágeno ordenado se adhieren mas (1.5-1.7 veces) y crecen mejor (2.3–2.6 veces) que sobre las matrices de colágeno no ordenado. Macrófagos Raw 264.7 teñidos con naranja de acridina revelaron mayor cantidad de células muertas sobra las matrices de colágeno no ordenado. Preosteoblástos MC3T3E1 (4 semanas en medio osteogénico) expresaron más fosfatasa alcalina (2.6 veces) y mineral en la matriz de colágeno. Los estudios preliminares sugieren que las matrices preparadas en base a colágeno natural podrían ser aplicadas en la regeneración del tejido. - Artículo
Acceso Abierto Changes induced by glucose in the plasma membrane properties of pancreatic islets(1990) Cortizo, Ana María; Paladini, A.; Díaz, G.B.; García, M.E.; Gagliardino, J.J.Partially purified membranes obtained from rat pancreatic isolated islets preincubated for 3 min with 3.3 and 16.6 mM glucose were labelled with 1,6-diphenyl-1,3,5-hexatriene to study fluorescence polarization. Other islets, incubated for 5 min with the same glucose concentration, were extracted and phospholipids separated by thin-layer chromatography. The composition of phospholipids of fatty acids was then studied by gas-liquid chromatography. Arrhenius plots of the microviscosity in membranes obtained from islets exhibited two components, a steeper slope below 18 degrees C and a gentler slope above 18 degrees C, indicating greater flow activation energy at temperatures below the transition point. Exposure of islets to 16.6 mM glucose significantly increased the flow activation energy (delta E), below and above the transition point. Islets incubated for 5 min with 16.6 mM glucose showed an increase in the percentage composition of 12:0 and 18:2 together with a decrease in the 20:2 W6 and 22:3 W3 fatty acids esterified to phospholipids. Regardless of these changes, no significant alterations occurred in the proportion of saturated fatty acids or in the double bond index; these measurements therefore did not account for the effects of glucose concentration in flow activation energy. The thermotropic changes reported here might be the consequence of some degree of disorder induced by glucose upon the membrane structure. This order alteration could either favor the membrane fusion which occurs during the emiocytosis or only reflects the consequence of such a process. - Artículo
Acceso Abierto Comparative Study of IGFBP Properties in Toad and Rat Sera(1993) Cortizo, Ana María; Braziunas, D.; Jasper, H.; Gagliardino, J.J.The levels ofIGF-Ihave been simultaneously measured byradioimmunoassayin samples of the toadBufo arenarumand of normal male Wistar rats. In addition, the different fractions of IGF-I binding proteins (IGFBP) and their binding properties have been identified by ligand blot and Scatchard analysis in the serum of both species. In the toad, we have measured levels of IGF-I (2.78 ± 0.48 ng/ml) similar to those previously reported in amphibians but far below those found in rats. IGFBP levels were estimated at 129 ± 23 and 4249 ± 321 pg/ml in toad and rat serum samples. Two main IGFBP fractions of 30-34 kDa, accompanied by a minor component of 24 kDa and seldom by another of 40 kDa, were identified in toad serum. In rat serum—as already reported—three bands of 40, 30, and 24 kDa were identified, the first being the main component and the last the minor one. The Scatchard analysis of a competitive binding assay showed two types of binding sites in toad serum: one of high affinity-low capacity (Ka1= 1.6 × 1010M-1;R1= 1.2 × 10-11M) and another with low affinity-high capacity (Ka2= 1.9 × 108M-1;R2= 1.9 × 10-10M). The percentage fraction of these binding sites occupied by IGF-I was 13.5%. The figures for K1and K2were lower and those for R1and R2were higher in rat than in toad serum. The percentage fraction of occupied ratIGFbinding sites was 3.6%. The IGF carrier levels (IGFBP5) estimated in our laboratory in samples of rat and toad serum gave figures that were almost 33 times lower in the latter than in the former. Hence, the fraction of free and bound IGF-I in toad and rat blood might be different. Our results provide new evidence of the presence and the properties of IGFBP in amphibians, confirming the wide distribution of this carrier among different species and its possible role as modulator of IGF-I biological effects. - Artículo
Acceso Abierto La diabetes altera el potencial osteogénico de células progenitoras de médula ósea: efectos del tratamiento con metformina(2012) Tolosa, M. J.; Chuguransky, S. R.; Schurman, León; Sedlinsky, Claudia; Cortizo, Ana María; McCarthy, Antonio Desmond; Molinuevo, María SilvinaEn este trabajo, estudiamos el efecto de una Diabetes inducida por destrucción parcial de la masa de células beta pancreáticas, sobre el compromiso osteogénico de células progenitoras de médula ósea (CPMO), y su modulación por el tratamiento oral con Metformina. Para ello utilizamos ratas Sprague Dawley, divididas en cuatro grupos: controles [C], controles tratadas con Metformina [M], diabéticas [D], y diabéticas tratadas con Metformina [DM]. La inducción de Diabetes se realizó, por inyección intraperitoneal sucesiva de ácido nicotínico y estreptozotocina. Sobre los cultivos de CPMO se evaluó la actividad específica de Fosfatasa Alcalina (FAL) y la producción de Colágeno tipo 1 (Col-1) en estado basal y en medio de diferenciación osteogénico luego de 15 días. A los 21 días, se evaluaron los depósitos de mineral extracelular. La FAL y el Col-1 de CPMO basales, no mostraron diferencias significativas entre los cuatro grupos experimentales. Al cabo de 15 días, las CPMO de ratas M mostraron un incremento en el Col-1 de 122 % respecto de C; D 30 % respecto de C y DM 68 % respecto de C. La FAL expresó un 171 % para M, 34 % para D; y 125 % para DM todos respecto de C. Luego de 21 días, se observó una disminución en la mineralización de las CPMO de D (65 % respecto del grupo C). El tratamiento con metformina incrementó la mineralización de las CPMO en todos los casos. En conclusión, en nuestro modelo experimental de Diabetes, ésta disminuye el potencial osteogénico de las CPMO, un efecto que es parcialmente revertido por el tratamiento oral con Metformina. Estos hallazgos podrían explicar, al menos en parte, las alteraciones óseas descriptas en el hueso asociadas con la Diabetes. - Artículo
Acceso Abierto Dilemas contemporáneos en torno a la construcción patrimonial y turística: el caso de dos localidades contrastantes en la provincia de Buenos Aires (Argentina)(2021) Pinassi, Andrés; Comparato, GabrielEl objetivo de esta investigación es analizar de manera comparada los procesos de construcción patrimonial y turística en las localidades bonaerenses de Tigre y Nicolás Levalle (Argentina), a la luz de los dilemas contemporáneos que se suscitan en el ámbito académico y de la gestión. En relación a la metodología, el trabajo adquiere un alcance explicativo y un enfoque mixto, con preponderancia cualitativa, caracterizándose por un razonamiento deductivo e inductivo que permite reflexionar de manera recíproca entre variables particulares y generales. Como resultado, las dos localidades indagadas fueron reconstruidas a partir de considerar: una acción histórica, relativa a los procesos de legitimación y selectividad del patrimonio y los atractivos turísticos; una acción dinámica, que puso en juego las transformaciones bajo nuevas formas de apropiación y uso del espacio; y una acción discursiva, que incorpora la dimensión simbólica y heterogénea en torno a la construcción patrimonial y turística, según la intervención de agentes específicos. A modo de conclusión, en esta investigación se enfatizó en los procesos de valorización turística del patrimonio, más allá de la descripción de los componentes histórico-culturales en sí mismos. En efecto, se buscó superar la mera casuística, para dar lugar a la articulación teórico-práctica en clave de contrastes. De allí que se visualizan diferentes discursos activados, que reflejan contextos históricos diversos, según la configuración socio-espacial de las localidades. Se observó que, dentro de un escenario de tensiones, objetivos e intereses distintos, elaccionar de ciertos actores sociales ha sido determinante para indagar los grados de consolidación y desarrollo turístico, al igual que los enfoques de gestión y los niveles de participación ciudadana. - Artículo
Acceso Abierto Efectos de los productos de glicación avanzada (AGEs) y alendronato sobre el desarrollo osteoclástico: posibles mecanismos de acción(2012) Gangoiti, María Virginia; McCarthy, Antonio Desmond; Cortizo, Ana MaríaIntroducción: En la Diabetes Mellitus se ha descripto un incremento en el riesgo de fracturas, las cuales podrían asociarse a la acumulación de productos de glicación avanzada (AGEs) que alteran la función de los osteoclastos (Oc), células gigantes multinucleadas encargadas de resorber el hueso. Los bifosfonatos (BP), drogas ampliamente usadas en enfermedades óseas, inhiben la actividad resortiva de los Oc, aunque su uso en pacientes diabéticos es controversial. Objetivo: Estudiar el efecto de AGEs y alendronato sobre el desarrollo de Oc en cultivo, así como los posibles mecanismos involucrados en la acción de estos agentes. Materiales y Métodos: Se cocultivaron macrófagos Raw264.7 y osteoblastos UMR-106 durante 8 días, con BSA o AGE (50-200 μg/ml), con o sin alendronato (10-8–10-4M). Se evaluó el efecto de estas condiciones de cultivo sobre la formación de Oc (número de los mismos, y actividad de fosfatasa ácida tartrato-resistente [TRAP]), la expresión de RAGE (Receptor de AGEs) en los Oc, y la expresión del ligando de RANK (RANKL) en los osteoblastos por inmunofluorescencia indirecta. Resultados: Los AGEs (50-200 μg/ml) inhibieron en forma dosis-dependiente la TRAP (10-30 %) y el número de osteoclastos generados (55 %), similarmente a lo inducido por bajas dosis de alendronato (10-8M–10-6M). La coincubación de bajas dosis de alendronato con 100 μg/ml de AGEs no indujo una inhibición adicional a la de los AGEs sobre la actividad de TRAP o el número de Oc. Altos niveles de alendronato (10-5M–10-4M) inhibieron la actividad TRAP (20-25 % respecto a BSA y 17 % respecto de AGEs), así como el número de Oc desarrollados en presencia de AGEs (16 % con respecto a AGEs). Los Oc incubados en presencia de 100 μg/ml AGEs mostraron un incremento significativo en la expresión de RAGE (152 % respecto de BSA), situación similar a la observada postincubación con alendronato 10-8M (130 % respecto de BSA). Por el contrario, altas dosis de alendronato (10-5M) no modificaron la expresión del RAGE en los cocultivos incubados con BSA (95 % respecto de BSA). Por otro lado, bajas dosis de alendronato en presencia de AGEs no alteraron la “up-regulation” del RAGE inducida por los AGEs (145 % respecto de BSA). Sin embargo, cuando los Oc se incubaron con AGEs y Ale 10-5M, esta dosis del bifosfonato bloqueó el efecto estimulante de los AGEs sobre la expresión de RAGE (105 % respecto de BSA). La incubación con 100 μg/ml AGE produjo una inhibición (50 % respecto de BSA), en la expresión del RANKL en los osteoblastos. El alendronato (10-8M–10-5M) indujo también una inhibición del RANKL en forma dosis dependiente (65-47 % respecto de BSA). Por otro lado en presencia de AGEs, el alendronato (10-8M–10-5M) no modificó la inhibición de la expresión del RANKL inducida por los AGEs (59-45 % del BSA). Conclusiones: Los AGEs y el alendronato inhiben el número y diferenciación de Oc en cultivo, con un efecto aditivo entre ambos a altas concentraciones de alendronato. También reducen la expresión de RANKL en osteoblastos, lo cual podría explicar parcialmente sus efectos sobre el reclutamiento y la maduración de Oc. Los AGEs y bajas dosis de alendronato aumentan la expresión de RAGE en Oc. - Artículo
Acceso Abierto Efectos in vivo del ranelato de estroncio sobre células progenitoras de médula ósea de ratas diabéticas(Asociación Argentina de Osteología y Metabolismo Mineral (AAOMM), 2016) Lino, Agustina Berenice; Fernández, Juan Manuel; Molinuevo, María Silvina; Cortizo, Ana María; McCarthy, Antonio DesmondLa diabetes mellitus (DM) crónica se asocia con reducción en el contenido mineral óseo (osteopenia y osteoporosis). El objetivo de este trabajo fue evaluar la acción del ranelato de estroncio (RaSr) administrado por vía oral a animales control y diabéticos, sobre el potencial osteogénico de células progenitoras de médula ósea (CPMO). Dieciséis ratas Wistar macho jóvenes se dividieron en dos grupos: controles (C) y diabéticas (D) con destrucción parcial de células b-pancreáticas mediante inyecciones intraperitoneales consecutivas de nicotinamida y estreptozotocina. Siete días después de la inyección, cada grupo se subdividió: sin tratamiento, o tratadas oralmente con RaSr (625 mg/kg/día) durante seis semanas, luego de lo cual los animales fueron sacrificados. Las CPMO se obtuvieron de ratas de los cuatro grupos, por lavados del canal diafisario medular (húmero o fémur o ambos) y cultivo hasta confluencia en DMEM-10% FBS. La proliferación celular se evaluó mediante el ensayo de MTT. Luego las CPMO se replaquearon e incubaron en un medio osteogénico durante 14 días (fosfatasa alcalina [FAL] y colágeno tipo 1) o 21 días (mi- * Correo electrónico: mccarthy@biol.unlp.edu.ar neralización). Las CPMO del grupo C+RaSr mostraron un aumento significativo versus control en la proliferación (133%) y en la diferenciación osteogénica (colágeno 143%, FAL 168%, mineralización 117%). La DM (grupo D) disminuyó significativamente la proliferación y diferenciación osteoblástica de las CPMO. El tratamiento con RaSr (grupo D+RaSr) previno completamente estos efectos antiosteogénicos de la DM. Así, en nuestro modelo experimental in vivo, la DM disminuye el potencial osteogénico de CPMO, efecto que puede ser prevenido por un tratamiento oral con RaSr. - Comunicacion
Acceso Abierto Effect of hypothyroidism on the composition and turnover rate of islet phospholipids(1984) Cortizo, Ana María; Garcia, M.E.; Pasquini, J.M.; Gagliardino, J.It has already been demonstrated that the pancreatic B cells of hypothyroid rats have a reduced capacity to release insulin in response to glucose (l). This impaired B cell function may be partly due to a diminished rate of glucose oxidation and net calcium uptake associated with ultrastructural alteration of the pancreatic islets (2). To identify further other factors responsible for this diminished B cell secretory function, we studied the composition and the turnover rate of phospholipids in islets obtained from hypothyroid rats. - Artículo
Acceso Abierto Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies(2010) Molinuevo, M. Silvina; Schurman, Leon; McCarthy, Antonio Desmond; Cortizo, Ana María; Tolosa, María J.; Gangoiti, M. Virginia; Arnol, Veronica; Sedlinsky, ClaudiaDiabetes mellitus is associated with bone loss. Patients with type 2 diabetes are frequently treated with oral antidiabetic drugs such as sulfonylureas, biguanides, and thiazolidinediones. Rosiglitazone treatment has been shown to increase adipogenesis in bone marrow and to induce bone loss. In this study we evaluated the effect of in vivo and in vitro treatment with metformin on bone marrow progenitor cells (BMPCs), as well as the involvement of AMPK pathway in its effects. The in vitro effect of coincubation with metformin and rosiglitazone on the adipogenic differentiation of BMPCs also was studied. In addition, we evaluated the effect of in vivo metformin treatment on bone regeneration in a model of parietal lesions in nondiabetic and streptozotocin-induced diabetic rats. We found that metformin administration both in vivo and in vitro caused an increase in alkaline phosphatase activity, type I collagen synthesis, osteocalcin expression, and extracellular calcium deposition of BMPCs. Moreover, metformin significantly activated AMPK in undifferentiated BMPCs. In vivo, metformin administration enhanced the expression of osteoblast-specific transcription factor Runx2/Cbfa1 and activation of AMPK in a time-dependent manner. Metformin treatment also stimulated bone lesion regeneration in control and diabetic rats. In vitro, metformin partially inhibited the adipogenic actions of rosiglitazone on BMPCs. In conclusion, our results indicate that metformin causes an osteogenic effect both in vivo and in vitro, possibly mediated by Runx2/Cbfa1 and AMPK activation, suggesting a possible action of metformin in a shift toward the osteoblastic differentiation of BMPCs. - Artículo
Embargado Effect of Surface Topography of Collagen Scaffolds on Cytotoxicity and Osteoblast Differentiation(2012) Cortizo, Ana María; Ruderman, Graciela; Correa, Gimena; Mogilner, Inés G.; Tolosa, Eduardo J.We have developed a biomimetic scaffold for tissue engineering using bovine collagen with different topographic characteristics, using matrices with random or parallel-arranged collagen fibres. Scaffolds were characterized by SEM, water contact angle and mechanical test. Biocompatiblitiy studies were performed with MC3T3E1 pre-osteoblasts, and adhesion, proliferation, differentiation and mineralization were assessed. Random film showed a smooth surface, while the ordered membrane revealed a grooved structure with channels separated 265 m from each other. Water contact angle was dependent on the direction of observation and the mechanical evaluation showed a lower resistance to traction and a greater ductility for the ordered membrane. Adhesion, proliferation, alkaline phosphatase activity and mineralization were significantly improved when cells were grown on the ordered-collagen matrix. There was no significant increase in pro-inflammatory cytokine release from cells grown on both random and ordered-collagen films. This material could be useful for bone tissue regeneration. - Artículo
Acceso Abierto Effects of fructose-induced metabolic syndrome on rat skeletal cells and tissue, and their responses to metformin treatment(2017) Felice, Juan Ignacio; Schurman, León; McCarthy, Antonio Desmond; Sedlinsky, Claudia; Aguirre, José Ignacio; Cortizo, Ana MaríaAims: Deleterious effects of metabolic syndrome (MS) on bone are still controversial. In this study we evaluated the effects of a fructose-induced MS, and/or an oral treatment with metformin on the osteogenic potential of bone marrow mesenchymal stromal cells (MSC), as well as on bone formation and architecture. Methods: 32 male 8 week-old Wistar rats were assigned to four groups: control (C), control plus oral metformin (CM), rats receiving 10% fructose in drinking water (FRD), and FRD plus metformin (FRDM). Samples were collected to measure blood parameters, and to perform pQCT analysis and static and dynamic histomorphometry. MSC were isolated to determine their osteogenic potential. Results: Metformin improved blood parameters in FRDM rats. pQCTand static and dynamic histomorphometry showed no significant differences in trabecular and cortical bone parameters among groups. FRD reduced TRAP expression and osteocyte density in trabecular bone and metformin only normalized osteocyte density. FRD decreased the osteogenic potential of MSC and metformin administration could revert some of these parameters. Conclusions: FRD-induced MS shows reduction in MSC osteogenic potential, in osteocyte density and in TRAP activity. Oral metformin treatment was able to prevent trabecular osteocyte loss and the reduction in extracellular mineralization induced by FRD-induced MS. - Artículo
Acceso Abierto Factores de crecimiento insulino símiles: estructura, bioactividad y métodos de ensayo(1998) Cortizo, Ana María; Mccarthy, AntonioEl sistema de los factores de crecimiento insulino-símiles (IGF) se halla involucrado en diferentes aspectos de la regulación celular y tisular, como así también en el desarrollo y el crecimiento corporal. Este sistema depende de la interacción entre ligandos (IGF-I, IGF-II), receptores (Tipo I, Tipo II), proteínas ligadoras o transportadoras (IGFBP-1 a -6), y proteasas específicas para las IGFBPs. La acción de los IGFs se encuentra regulada por diferentes factores y estímulos, tales como la hormona de crecimiento, que actúan a diversos niveles. El desarrollo de nuevos métodos para analizar los diferentes componentes del sistema de los IGFs ha aportado elementos adicionales para la evaluación, diagnóstico y seguimiento de pacientes con alteraciones del crecimiento.
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