The Experts below are selected from a list of 1074 Experts worldwide ranked by ideXlab platform
Paredes Lazo, Dunia Teresita - One of the best experts on this subject based on the ideXlab platform.
-
Histological alterations due to Hypervitaminosis A in the long bones of newly born Sprague Dawley rats
Universidad de Ciencias Médicas de Pinar del Río, 2018Co-Authors: Hernández Díaz Rayza, Sanabria Negrín, José Guillermo, Zaldívar Garrit Isvel, Llanuch Lara Margarita, Paredes Lazo, Dunia TeresitaAbstract:Introducción: el consumo en altas dosis de vitamina A a dosis mínima teratogénica podría ser causa posible de alteraciones histológicas del hueso durante el crecimiento intrauterino. Objetivo: evaluar el efecto de la hipervitaminosis A inducida en ratas sobre los huesos largos de la descendencia. Método: se realizó un estudio experimental en ratas Sprague Dawley preñadas: dos grupos con tres animales c/u: control negativo y casos con dosis de VA 50 µg/g durante los primeros 16 días de preñez entre septiembre 2015 y febrero 2016. Se tomaron los fémures derechos de todas las ratas (n=12 en cada grupo) con 2 horas de nacidas. Los huesos fueron descalcificados, procesados en parafina y teñidos con hematoxilina/eosina. Se realizó morfometría de corte longitudinal de fémur derecho en el punto medio de las diáfisis del grosor del periostio, endostio, cortical y total de la diáfisis. Las variables cualitativas fueron resumidas mediante frecuencias y las cuantitativas, mediante la media y desviación estándar. Las comparaciones se verificaron mediante las pruebas de X2 y T de Student al 95 % de certezaResultados: tanto el grosor del periostio, como el del endostio, de la cortical y el diámetro de la diáfisis del fémur mostraron disminuciones altamente significativas (p<0.0001) en la comparación de medias entre los grupos de estudio y control. El cartílago endocondral aumentado, y la dilatación de los vasos medulares fueron más frecuente entre los casos (p<0.0001) Conclusiones: la hipervitaminosis A durante la preñez en ratas Sprague Dawley reduce el tamaño del fémur en la descendencia.Introduction: the consumption in high doses of vitamin-A at a minimum teratogenic dose could be a possible cause of histological alterations of bones during intrauterine growth.Objective: to assess the effect of Hypervitaminosis A induced in rats on the long bones of offspring.Method: an experimental study was conducted on pregnant Sprague Dawley rats: two groups with three animals each: negative control and cases with VA dose 50 μg / g during the first 16 days of pregnancy between September 2015 and February 2016. The right femurs of all rats were taken (n = 12 in each group) 2 hours after birth. The bones were decalcified, processed in paraffin and stained with haematoxylin / eosin. Longitudinal section morphometry of the right femur was performed at the midpoint of the diaphysis of the thickness of the periosteum, endosteum, cortical and total of the diaphysis. The qualitative variables were summarized by frequencies and the quantitative using the mean and standard deviation. The comparisons were verified by X2 and Student's-T tests at 95 % certainty.Results: thickness of the periosteum and endosteum, cortex thickness, and diaphysis of the femur showed highly significant decreases (p <0.0001) when comparing the means between the study and control groups. Increased endochondral cartilage and dilation of medullar vessels were more frequent among cases (p <0.0001)Conclusions: Hypervitaminosis A during pregnancy in Sprague Dawley rats reduces the size of the femur in offspring
-
Hipervitaminosis A y lesiones hísticas hepáticas en ratas Sprague Dawley recién nacidas
'Massachusetts Medical Society', 2018Co-Authors: Paredes Lazo, Dunia Teresita, Sanabria Negrín, José Guillermo, Zaldívar Garrit Isvel, Crespo Dueñas Amado, Cruz Hernández, Inalbis De La CaridadAbstract:Introduction: Hypervitaminosis A is capable of causing morpho-histological changes in different organs and tissues that can cause serious consequences in pregnant women and the product of their conception.Objective: to evaluate the effects of Hypervitaminosis A during pregnancy on liver tissue in broods of Sprague Dawley rats.Method: an experimental study was carried out using Sprague Dawley rats bred in two groups, with two rats each one, between September 2015 and February 2016. Control group: no treatment. Experimental group: was given vitamin A, 50 μg / g during the first 16 days of pregnancy; 2 hours after the litter was born (n = 12 per group) the livers were analyzed by histology and morphometry. Qualitative and quantitative variables were studied. The first ones were compared by the X2 test; the quantitative ones through a test of means difference. All were verified at 95% of certainty.Results: in the treated group a significant increase (p
-
Hipervitaminosis A y lesiones hísticas hepáticas en ratas Sprague Dawley recién nacidas
Universidad de Ciencias Médicas de Pinar del Río, 2018Co-Authors: Paredes Lazo, Dunia Teresita, Sanabria Negrín, José Guillermo, Zaldívar Garrit Isvel, Crespo Dueñas Amado, Cruz Hernández, Inalbis De La CaridadAbstract:Introduction: Hypervitaminosis A is capable of causing morpho-histological changes in different organs and tissues that can cause serious consequences in pregnant women and the product of their conception.Objective: to evaluate the effects of Hypervitaminosis A during pregnancy on liver tissue in broods of Sprague Dawley rats.Method: an experimental study was carried out using Sprague Dawley rats bred in two groups, with two rats each one, between September 2015 and February 2016. Control group: no treatment. Experimental group: was given vitamin A, 50 μg / g during the first 16 days of pregnancy; 2 hours after the litter was born (n = 12 per group) the livers were analyzed by histology and morphometry. Qualitative and quantitative variables were studied. The first ones were compared by the X2 test; the quantitative ones through a test of means difference. All were verified at 95% of certainty.Results: in the treated group a significant increase (p <0.05) of vacuolar hepatocyte degeneration, hyperplasia of the Küpffer cells and sinusoidal congestion were found. The hepatocellular necrosis and the congestion of the central veins were not different. A significant increase (p <0.05) in nuclear volume was found in the 3 zones of the hepatic acinus.Conclusions: Hypervitaminosis A (50μg / g), during pregnancy in rats, produces liver alterations in newborns, therefore a balance in the intake of vitamin A, especially during pregnancy, it is necessary to contribute to a better quality of pregnant women, in order to improve Maternal and Child Program of the country.Introducción: la hipervitaminosis A es capaz de provocar cambios morfo-histológicos en diferentes órganos y tejidos que pueden provocar graves consecuencias en las gestantes y el producto de su concepción.Objetivo: evaluar los efectos de la hipervitaminosis A durante la gestación sobre el tejido hepático en crías de ratas Sprague Dawley.Método: se realizó un estudio experimental utilizando ratas Sprague Dawley gestadas en dos grupos, con dos ratas en cada uno entre septiembre 2015 y febrero 2016. Grupo control: sin tratamiento. Grupo experimental: recibió vitamina A, 50 µg/g durante los primeros 16 días de preñez. A las dos horas de nacidas las crías (n=12 por grupo) fueron analizados los hígados mediante histología y morfometría. Se estudiaron variables cualitativas y cuantitativas. Las primeras fueron comparadas mediante le prueba de X2; las cuantitativas, mediante prueba de diferencia de medias. Todas se verificaron al 95 % de certeza.Resultados: en el grupo tratado se encontró incremento significativo (p<0.05) de degeneración vacuolar hepatocitaria, hiperplasia de las células de Küpffer y la congestión sinusoidal. La necrosis hepatocelular y la congestión de las venas centrales no fueron diferentes. Se encontró aumento significativo (p<0.05) del volumen nuclear en las 3 zonas del acino hepático. Conclusiones: la hipervitaminosis A (50µg/g), durante el embarazo en ratas, produce alteraciones hepáticas en las crías recién nacidas, por tanto, es necesario un balance en la ingestión de vitamina A, sobre todo durante el embarazo, para contribuir a una mejor calidad de las gestantes, a favor de mejorar el Programa Materno Infantil del país
Håkan Melhus - One of the best experts on this subject based on the ideXlab platform.
-
bones in human cyp26b1 deficiency and rats with Hypervitaminosis a phenocopy vegfa overexpression
Bone reports, 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Arie Van Haeringen, Maria Norgård, Håkan Melhus, Stephen P Robertson, Goran AnderssonAbstract:Abstract Angulated femurs are present prenatally both in CYP26B1 deficient humans with a reduced capacity to degrade retinoic acid (RA, the active metabolite of vitamin A), and mice overexpressing vascular endothelial growth factor a (Vegfa). Since excessive ingestion of vitamin A is known to induce spontaneous fractures and as the Vegfa-induced femur angulation in mice appears to be caused by intrauterine fractures, we analyzed bones from a CYP26B1 deficient human and rats with Hypervitaminosis A to further explore Vegfa as a mechanistic link for the effect of vitamin A on bone. We show that bone from a human with CYP26B1 mutations displayed periosteal osteoclasts in piles within deep resorption pits, a pathognomonic sign of Hypervitaminosis A. Analysis of the human angulated fetal femur revealed excessive bone formation in the marrow cavity and abundant blood vessels. Normal human endothelial cells showed disturbed cell-cell junctions and increased CYP26B1 and VEGFA expression upon RA exposure. Studies in rats showed increased plasma and tissue Vegfa concentrations and signs of bone marrow microhemorrhage on the first day of excess dietary vitamin A intake. Subsequently Hypervitaminosis A rats displayed excess bone formation, fibrosis and an increased number of megakaryocytes in the bone marrow, which are known characteristics of Vegfa overexpression. This study supports the notion that the skeletal phenotype in CYP26B1 deficient human bone is caused by excess RA. Our findings suggest that an initial part of the vitamin A mechanism causing bone alterations is mediated by excess Vegfa and disturbed bone marrow microvessel integrity.
-
studies of indirect and direct effects of Hypervitaminosis a on rat bone by comparing free access to food and pair feeding
Upsala Journal of Medical Sciences, 2018Co-Authors: Thomas Lind, Monica P Lind, Håkan MelhusAbstract:Background: The most prominent features of Hypervitaminosis A in rats are spontaneous fractures and anorexia. Since caloric restriction induces alterations in bone, some effects could be secondary ...
-
Bones in human CYP26B1 deficiency and rats with Hypervitaminosis A phenocopy Vegfa overexpression
'Elsevier BV', 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Maria Norgård, Håkan Melhus, Stephen P Robertson, Arie Van Haeringen, Goran AnderssonAbstract:Angulated femurs are present prenatally both in CYP26B1 deficient humans with a reduced capacity to degrade retinoic acid (RA, the active metabolite of vitamin A), and mice overexpressing vascular endothelial growth factor a (Vegfa). Since excessive ingestion of vitamin A is known to induce spontaneous fractures and as the Vegfa-induced femur angulation in mice appears to be caused by intrauterine fractures, we analyzed bones from a CYP26B1 deficient human and rats with Hypervitaminosis A to further explore Vegfa as a mechanistic link for the effect of vitamin A on bone. We show that bone from a human with CYP26B1 mutations displayed periosteal osteoclasts in piles within deep resorption pits, a pathognomonic sign of Hypervitaminosis A. Analysis of the human angulated fetal femur revealed excessive bone formation in the marrow cavity and abundant blood vessels. Normal human endothelial cells showed disturbed cell-cell junctions and increased CYP26B1 and VEGFA expression upon RA exposure. Studies in rats showed increased plasma and tissue Vegfa concentrations and signs of bone marrow microhemorrhage on the first day of excess dietary vitamin A intake. Subsequently Hypervitaminosis A rats displayed excess bone formation, fibrosis and an increased number of megakaryocytes in the bone marrow, which are known characteristics of Vegfa overexpression. This study supports the notion that the skeletal phenotype in CYP26B1 deficient human bone is caused by excess RA. Our findings suggest that an initial part of the vitamin A mechanism causing bone alterations is mediated by excess Vegfa and disturbed bone marrow microvessel integrity. Keywords: CYP26B1, Vitamin A, VEGFA, Microhemorrhage, Human, Rat, Bon
-
Osteocyte markers in RA and RAR antagonist treated MC3T3-E1 cells and periosteal and serum phenotype in vitamin A treated rats.
2013Co-Authors: Thomas Lind, Goran Andersson, Anders Sundqvist, Gunnar Pejler, Annica Jacobson, Håkan MelhusAbstract:QRT-PCR analysis of Tnfsf11 (RANKL) and Dmp1, (A) Phex, Sost and Fgf23 (B) expression at day 14 and 21 during a mineralization experiment of MC3T3-E1 cells treated with 400 nM RA or 1 µM AGN. (C) Representative Western blot analysis of Phex, Dmp1 and full length RANKL at day 14 and 21 of MC3T3-E1 cells treated as in (A) and quantification of Western bands relative to Actb (relative ratio). (D) Dmp1 and Cathepsin K (CatK) immunohistochemical staining at the diaphyseal periosteal site in rats suffering from Hypervitaminosis A and in control rats. Upper panel: Arrow heads indicate Dmp1 negative osteocytes close to the periosteum (Ps) in control rat bone and arrows indicate Dmp1 positive osteocytes close to the periosteum in Hypervitaminosis A rat bone. Lower panel: only Vitamin A animals show clear CatK staining at the Ps site. (E) Serum Fgf23 and phosphate levels in rats from (D). Means +/– SD, * p
-
subclinical Hypervitaminosis a in rat measurements of bone mineral density bmd do not reveal adverse skeletal changes
Chemico-Biological Interactions, 2006Co-Authors: P M Lind, Monika Ronn, S Johansson, Håkan MelhusAbstract:We have previously shown that subclinical Hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-fiv ...
Cruz Hernández, Inalbis De La Caridad - One of the best experts on this subject based on the ideXlab platform.
-
Hipervitaminosis A y lesiones hísticas hepáticas en ratas Sprague Dawley recién nacidas
'Massachusetts Medical Society', 2018Co-Authors: Paredes Lazo, Dunia Teresita, Sanabria Negrín, José Guillermo, Zaldívar Garrit Isvel, Crespo Dueñas Amado, Cruz Hernández, Inalbis De La CaridadAbstract:Introduction: Hypervitaminosis A is capable of causing morpho-histological changes in different organs and tissues that can cause serious consequences in pregnant women and the product of their conception.Objective: to evaluate the effects of Hypervitaminosis A during pregnancy on liver tissue in broods of Sprague Dawley rats.Method: an experimental study was carried out using Sprague Dawley rats bred in two groups, with two rats each one, between September 2015 and February 2016. Control group: no treatment. Experimental group: was given vitamin A, 50 μg / g during the first 16 days of pregnancy; 2 hours after the litter was born (n = 12 per group) the livers were analyzed by histology and morphometry. Qualitative and quantitative variables were studied. The first ones were compared by the X2 test; the quantitative ones through a test of means difference. All were verified at 95% of certainty.Results: in the treated group a significant increase (p
-
Hipervitaminosis A y lesiones hísticas hepáticas en ratas Sprague Dawley recién nacidas
Universidad de Ciencias Médicas de Pinar del Río, 2018Co-Authors: Paredes Lazo, Dunia Teresita, Sanabria Negrín, José Guillermo, Zaldívar Garrit Isvel, Crespo Dueñas Amado, Cruz Hernández, Inalbis De La CaridadAbstract:Introduction: Hypervitaminosis A is capable of causing morpho-histological changes in different organs and tissues that can cause serious consequences in pregnant women and the product of their conception.Objective: to evaluate the effects of Hypervitaminosis A during pregnancy on liver tissue in broods of Sprague Dawley rats.Method: an experimental study was carried out using Sprague Dawley rats bred in two groups, with two rats each one, between September 2015 and February 2016. Control group: no treatment. Experimental group: was given vitamin A, 50 μg / g during the first 16 days of pregnancy; 2 hours after the litter was born (n = 12 per group) the livers were analyzed by histology and morphometry. Qualitative and quantitative variables were studied. The first ones were compared by the X2 test; the quantitative ones through a test of means difference. All were verified at 95% of certainty.Results: in the treated group a significant increase (p <0.05) of vacuolar hepatocyte degeneration, hyperplasia of the Küpffer cells and sinusoidal congestion were found. The hepatocellular necrosis and the congestion of the central veins were not different. A significant increase (p <0.05) in nuclear volume was found in the 3 zones of the hepatic acinus.Conclusions: Hypervitaminosis A (50μg / g), during pregnancy in rats, produces liver alterations in newborns, therefore a balance in the intake of vitamin A, especially during pregnancy, it is necessary to contribute to a better quality of pregnant women, in order to improve Maternal and Child Program of the country.Introducción: la hipervitaminosis A es capaz de provocar cambios morfo-histológicos en diferentes órganos y tejidos que pueden provocar graves consecuencias en las gestantes y el producto de su concepción.Objetivo: evaluar los efectos de la hipervitaminosis A durante la gestación sobre el tejido hepático en crías de ratas Sprague Dawley.Método: se realizó un estudio experimental utilizando ratas Sprague Dawley gestadas en dos grupos, con dos ratas en cada uno entre septiembre 2015 y febrero 2016. Grupo control: sin tratamiento. Grupo experimental: recibió vitamina A, 50 µg/g durante los primeros 16 días de preñez. A las dos horas de nacidas las crías (n=12 por grupo) fueron analizados los hígados mediante histología y morfometría. Se estudiaron variables cualitativas y cuantitativas. Las primeras fueron comparadas mediante le prueba de X2; las cuantitativas, mediante prueba de diferencia de medias. Todas se verificaron al 95 % de certeza.Resultados: en el grupo tratado se encontró incremento significativo (p<0.05) de degeneración vacuolar hepatocitaria, hiperplasia de las células de Küpffer y la congestión sinusoidal. La necrosis hepatocelular y la congestión de las venas centrales no fueron diferentes. Se encontró aumento significativo (p<0.05) del volumen nuclear en las 3 zonas del acino hepático. Conclusiones: la hipervitaminosis A (50µg/g), durante el embarazo en ratas, produce alteraciones hepáticas en las crías recién nacidas, por tanto, es necesario un balance en la ingestión de vitamina A, sobre todo durante el embarazo, para contribuir a una mejor calidad de las gestantes, a favor de mejorar el Programa Materno Infantil del país
Joost G. J. Hoenderop - One of the best experts on this subject based on the ideXlab platform.
-
Basic Science Articles Hypervitaminosis D Mediates Compensatory Ca2 Hyperabsorption in TRPV5 Knockout Mice
2015Co-Authors: Kirsten Y. Renkema, Tom Nijenhuis, Harrie Weinans, René J. M. Bindels, Joost G. J. HoenderopAbstract:Vitamin D plays an important role in Ca2 homeostasis by controlling Ca2 (re)absorption in intestine, kidney, and bone. The epithelial Ca2 channel TRPV5 mediates the Ca2 entry step in active Ca2 reabsorption. TRPV5 knockout (TRPV5/) mice show impaired Ca2 reabsorption, hypercalciuria, Hypervitaminosis D, and intestinal hyperabsorption of Ca2. Moreover, these mice demonstrate upregulation of intestinal TRPV6 and calbindin-D9K expression compared with wild-type mice. For addressing the role of the observed Hypervitaminosis D in the maintenance of Ca2 homeostasis and the regulation of expression levels of the Ca2 transport proteins in kidney and intestine, TRPV5/25-hydroxyvitamin-D3-1-hydroxylase double knockout (TRPV5//1-OHase/) mice, which show undetectable serum 1,25(OH)2D3 levels, were generated. TRPV5 1-OHase/ mice displayed a significant hypocalcemia compared with wild-type mice (1.10 0.02 and 2.54 0.01 mM, respectively; P < 0.05). mRNA levels of renal calbindin-D28K (7 2%), calbindin-D9K (32 4%), Na /Ca2 exchanger (12 2%), and intestinal TRPV6 (40 8%) and calbindin-D9K (26 4%) expression levels were decreased compared with wild-type mice. Hyperparathyroidism and rickets were present in TRPV5//1-OHase/ mice, more pronounced than observed in single TRPV5 or 1-OHase knockout mice. It is interesting that a renal Ca2 leak, as demonstrated in TRPV5/ mice, persisted in TRPV5//1-OHase/mice, but a compensatory upregulation of intestinal Ca2 transporters was abolished. In conclusion, the elevation of serum 1,25(OH)2D3 levels in TRPV5 /mice is responsible for the upregulation of intestinal Ca2 transporters and Ca2 hyperabsorption. Hypervitaminosis D, therefore, is of crucial importance to maintain normocalcemia in impaired Ca2 reabsorption in TRPV5/ mice
-
Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice.
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Kirsten Y. Renkema, Tom Nijenhuis, Bram C. J. Van Der Eerden, Annemiete W.c.m. Van Der Kemp, Harrie Weinans, Johannes P.t.m. Van Leeuwen, René J. M. Bindels, Joost G. J. HoenderopAbstract:Vitamin D plays an important role in Ca(2+) homeostasis by controlling Ca(2+) (re)absorption in intestine, kidney, and bone. The epithelial Ca(2+) channel TRPV5 mediates the Ca(2+) entry step in active Ca(2+) reabsorption. TRPV5 knockout (TRPV5(-/-)) mice show impaired Ca(2+) reabsorption, hypercalciuria, Hypervitaminosis D, and intestinal hyperabsorption of Ca(2+). Moreover, these mice demonstrate upregulation of intestinal TRPV6 and calbindin-D(9K) expression compared with wild-type mice. For addressing the role of the observed Hypervitaminosis D in the maintenance of Ca(2+) homeostasis and the regulation of expression levels of the Ca(2+) transport proteins in kidney and intestine, TRPV5/25-hydroxyvitamin-D(3)-1alpha-hydroxylase double knockout (TRPV5(-/-)/1alpha-OHase(-/-)) mice, which show undetectable serum 1,25(OH)(2)D(3) levels, were generated. TRPV5(-/-)/1alpha-OHase(-/-) mice displayed a significant hypocalcemia compared with wild-type mice (1.10 +/- 0.02 and 2.54 +/- 0.01 mM, respectively; P < 0.05). mRNA levels of renal calbindin-D(28K) (7 +/- 2%), calbindin-D(9K) (32 +/- 4%), Na(+)/Ca(2+) exchanger (12 +/- 2%), and intestinal TRPV6 (40 +/- 8%) and calbindin-D(9K) (26 +/- 4%) expression levels were decreased compared with wild-type mice. Hyperparathyroidism and rickets were present in TRPV5(-/-)/1alpha-OHase(-/-) mice, more pronounced than observed in single TRPV5 or 1alpha-OHase knockout mice. It is interesting that a renal Ca(2+) leak, as demonstrated in TRPV5(-/-) mice, persisted in TRPV5(-/-)/1alpha-OHase(-/-) mice, but a compensatory upregulation of intestinal Ca(2+) transporters was abolished. In conclusion, the elevation of serum 1,25(OH)(2)D(3) levels in TRPV5(-/-) mice is responsible for the upregulation of intestinal Ca(2+) transporters and Ca(2+) hyperabsorption. Hypervitaminosis D, therefore, is of crucial importance to maintain normocalcemia in impaired Ca(2+) reabsorption in TRPV5(-/-) mice.
Thomas Lind - One of the best experts on this subject based on the ideXlab platform.
-
bones in human cyp26b1 deficiency and rats with Hypervitaminosis a phenocopy vegfa overexpression
Bone reports, 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Arie Van Haeringen, Maria Norgård, Håkan Melhus, Stephen P Robertson, Goran AnderssonAbstract:Abstract Angulated femurs are present prenatally both in CYP26B1 deficient humans with a reduced capacity to degrade retinoic acid (RA, the active metabolite of vitamin A), and mice overexpressing vascular endothelial growth factor a (Vegfa). Since excessive ingestion of vitamin A is known to induce spontaneous fractures and as the Vegfa-induced femur angulation in mice appears to be caused by intrauterine fractures, we analyzed bones from a CYP26B1 deficient human and rats with Hypervitaminosis A to further explore Vegfa as a mechanistic link for the effect of vitamin A on bone. We show that bone from a human with CYP26B1 mutations displayed periosteal osteoclasts in piles within deep resorption pits, a pathognomonic sign of Hypervitaminosis A. Analysis of the human angulated fetal femur revealed excessive bone formation in the marrow cavity and abundant blood vessels. Normal human endothelial cells showed disturbed cell-cell junctions and increased CYP26B1 and VEGFA expression upon RA exposure. Studies in rats showed increased plasma and tissue Vegfa concentrations and signs of bone marrow microhemorrhage on the first day of excess dietary vitamin A intake. Subsequently Hypervitaminosis A rats displayed excess bone formation, fibrosis and an increased number of megakaryocytes in the bone marrow, which are known characteristics of Vegfa overexpression. This study supports the notion that the skeletal phenotype in CYP26B1 deficient human bone is caused by excess RA. Our findings suggest that an initial part of the vitamin A mechanism causing bone alterations is mediated by excess Vegfa and disturbed bone marrow microvessel integrity.
-
studies of indirect and direct effects of Hypervitaminosis a on rat bone by comparing free access to food and pair feeding
Upsala Journal of Medical Sciences, 2018Co-Authors: Thomas Lind, Monica P Lind, Håkan MelhusAbstract:Background: The most prominent features of Hypervitaminosis A in rats are spontaneous fractures and anorexia. Since caloric restriction induces alterations in bone, some effects could be secondary ...
-
Bones in human CYP26B1 deficiency and rats with Hypervitaminosis A phenocopy Vegfa overexpression
'Elsevier BV', 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Maria Norgård, Håkan Melhus, Stephen P Robertson, Arie Van Haeringen, Goran AnderssonAbstract:Angulated femurs are present prenatally both in CYP26B1 deficient humans with a reduced capacity to degrade retinoic acid (RA, the active metabolite of vitamin A), and mice overexpressing vascular endothelial growth factor a (Vegfa). Since excessive ingestion of vitamin A is known to induce spontaneous fractures and as the Vegfa-induced femur angulation in mice appears to be caused by intrauterine fractures, we analyzed bones from a CYP26B1 deficient human and rats with Hypervitaminosis A to further explore Vegfa as a mechanistic link for the effect of vitamin A on bone. We show that bone from a human with CYP26B1 mutations displayed periosteal osteoclasts in piles within deep resorption pits, a pathognomonic sign of Hypervitaminosis A. Analysis of the human angulated fetal femur revealed excessive bone formation in the marrow cavity and abundant blood vessels. Normal human endothelial cells showed disturbed cell-cell junctions and increased CYP26B1 and VEGFA expression upon RA exposure. Studies in rats showed increased plasma and tissue Vegfa concentrations and signs of bone marrow microhemorrhage on the first day of excess dietary vitamin A intake. Subsequently Hypervitaminosis A rats displayed excess bone formation, fibrosis and an increased number of megakaryocytes in the bone marrow, which are known characteristics of Vegfa overexpression. This study supports the notion that the skeletal phenotype in CYP26B1 deficient human bone is caused by excess RA. Our findings suggest that an initial part of the vitamin A mechanism causing bone alterations is mediated by excess Vegfa and disturbed bone marrow microvessel integrity. Keywords: CYP26B1, Vitamin A, VEGFA, Microhemorrhage, Human, Rat, Bon
-
Mcpt4-/- mice in ovariectomy- and vitamin A-induced osteoporosis models.
2016Co-Authors: Thomas Lind, Annmarie Gustafson, Goran Andersson, Gabriela Calounova, Annica Rasmusson, Kenneth B. Jonsson, Sara Wernersson, Magnus Åbrink, Sune LarssonAbstract:A) Body weight 6 weeks after sham (n = 5) or ovariectomy (OVX) in wt (sham, OVX) (n = 7) and Mcpt4-/- (OVX) (n = 4). B) Femur trabecular density and cortical thickness in animals as described in (A). C) Body weight after 1 week of Hypervitaminosis A at the age of 7 months. Number of animals in each group are wt controls (Cont, wt; n = 6), Mcpt4-/- controls (Cont, Mcpt4-/-; n = 5), controls vitamin A (Vitamin A, wt; n = 5) and vitamin A Mcpt4-/- (Vitamin A, Mcpt4-/-; n = 5). D) Femur diaphyseal total cross sectional area (Total area) after 1 week of Hypervitaminosis A. Results are given as means ± SD. p < 0.05 *, p < 0.01 ** and p < 0.001 *** vs. wt/sham/Cont., p < 0.05 # and p < 0.001 ### vs. Cont Mcpt4-/-, p < 0.001 ¤¤¤ vs. Cont wt.
-
Osteocyte markers in RA and RAR antagonist treated MC3T3-E1 cells and periosteal and serum phenotype in vitamin A treated rats.
2013Co-Authors: Thomas Lind, Goran Andersson, Anders Sundqvist, Gunnar Pejler, Annica Jacobson, Håkan MelhusAbstract:QRT-PCR analysis of Tnfsf11 (RANKL) and Dmp1, (A) Phex, Sost and Fgf23 (B) expression at day 14 and 21 during a mineralization experiment of MC3T3-E1 cells treated with 400 nM RA or 1 µM AGN. (C) Representative Western blot analysis of Phex, Dmp1 and full length RANKL at day 14 and 21 of MC3T3-E1 cells treated as in (A) and quantification of Western bands relative to Actb (relative ratio). (D) Dmp1 and Cathepsin K (CatK) immunohistochemical staining at the diaphyseal periosteal site in rats suffering from Hypervitaminosis A and in control rats. Upper panel: Arrow heads indicate Dmp1 negative osteocytes close to the periosteum (Ps) in control rat bone and arrows indicate Dmp1 positive osteocytes close to the periosteum in Hypervitaminosis A rat bone. Lower panel: only Vitamin A animals show clear CatK staining at the Ps site. (E) Serum Fgf23 and phosphate levels in rats from (D). Means +/– SD, * p