RESUMEN
PURPOSE: To investigate inhibitory effect of Astragalus polysaccharide (APS) on osteoporosis in ovariectomized rats by regulating FoxO3a/Wnt2 signaling pathway. METHODS: Postmenopausal osteoporosis (PMOP) animal model was developed by excising the bilateral ovaries of rats. The model rats were administered with APS (200 mg/kg, 400 mg/kg, 800 mg/kg) by intragastric administration once daily for 12 weeks. Bone density, bone metabolism index and oxidative stress index were measured in all groups. Furthermore, the regulation of APS of FoxO3a / Wnt2 signaling pathway was observed. RESULTS: APS has an estrogen-like effect, which can increase bone mass, lower serum ALP and BGP values, increase blood calcium content, and increase bone density of the femur and vertebrae in rats. At the same time, APS can increase the bone mineral content of the femur, increase the maximum stress, maximum load and elastic modulus of the ovariectomized rats, improve oxidative stress in rats by increasing the gene expression of ß-catenin and Wnt2 mRNA and inhibiting the gene expression of FoxO3a mRNA. CONCLUSION: Astragalus polysaccharide can effectively alleviate oxidative stress-mediated osteoporosis in ovariectomized rats, which may be related to its regulation of FoxO3a/Wnt2/ß-catenin pathway.
Asunto(s)
Planta del Astrágalo/química , Proteína Forkhead Box O3/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Polisacáridos/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Densidad Ósea/efectos de los fármacos , Femenino , Fémur/efectos de los fármacos , Fémur/metabolismo , Proteína Forkhead Box O3/análisis , Expresión Génica/efectos de los fármacos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/análisis , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/efectos de los fármacos , Osteoporosis/metabolismo , Ovariectomía , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Distribución Aleatoria , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Reproducibilidad de los Resultados , Resultado del Tratamiento , Vía de Señalización Wnt/fisiología , Proteína wnt2/análisis , Proteína wnt2/efectos de los fármacos , beta Catenina/análisis , beta Catenina/efectos de los fármacosRESUMEN
Abstract Purpose: To investigate inhibitory effect of Astragalus polysaccharide (APS) on osteoporosis in ovariectomized rats by regulating FoxO3a/Wnt2 signaling pathway. Methods: Postmenopausal osteoporosis (PMOP) animal model was developed by excising the bilateral ovaries of rats. The model rats were administered with APS (200 mg/kg, 400 mg/kg, 800 mg/kg) by intragastric administration once daily for 12 weeks. Bone density, bone metabolism index and oxidative stress index were measured in all groups. Furthermore, the regulation of APS of FoxO3a / Wnt2 signaling pathway was observed. Results: APS has an estrogen-like effect, which can increase bone mass, lower serum ALP and BGP values, increase blood calcium content, and increase bone density of the femur and vertebrae in rats. At the same time, APS can increase the bone mineral content of the femur, increase the maximum stress, maximum load and elastic modulus of the ovariectomized rats, improve oxidative stress in rats by increasing the gene expression of β-catenin and Wnt2 mRNA and inhibiting the gene expression of FoxO3a mRNA. Conclusion: Astragalus polysaccharide can effectively alleviate oxidative stress-mediated osteoporosis in ovariectomized rats, which may be related to its regulation of FoxO3a/Wnt2/β-catenin pathway.
Asunto(s)
Animales , Femenino , Osteoporosis/tratamiento farmacológico , Polisacáridos/farmacología , Planta del Astrágalo/química , Vía de Señalización Wnt/efectos de los fármacos , Proteína Forkhead Box O3/efectos de los fármacos , Osteoporosis/metabolismo , Valores de Referencia , Ovariectomía , Distribución Aleatoria , Densidad Ósea/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Reproducibilidad de los Resultados , Resultado del Tratamiento , Ratas Sprague-Dawley , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Proteína wnt2/análisis , Proteína wnt2/efectos de los fármacos , beta Catenina/análisis , beta Catenina/efectos de los fármacos , Fémur/efectos de los fármacos , Fémur/metabolismo , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/análisis , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa , Vía de Señalización Wnt/fisiología , Proteína Forkhead Box O3/análisisRESUMEN
The Wnt canonical ligands elicit the activation of ß-catenin transcriptional activity, a response dependent on, but not limited to, ß-catenin stabilization through the inhibition of GSK3 activity. Two mechanisms have been proposed for this inhibition, one dependent on the binding and subsequent block of GSK3 to LRP5/6 Wnt coreceptor and another one on its sequestration into multivesicular bodies (MVBs). Here we report that internalization of the GSK3-containing Wnt-signalosome complex into MVBs is dependent on the dissociation of p120-catenin/cadherin from this complex. Disruption of cadherin-LRP5/6 interaction is controlled by cadherin phosphorylation and requires the previous separation of p120-catenin; thus, p120-catenin and cadherin mutants unable to dissociate from the complex block GSK3 sequestration into MVBs. These mutants substantially inhibit, but do not completely prevent, the ß-catenin upregulation caused by Wnt3a. These results, besides elucidating how GSK3 is sequestered into MVBs, support this mechanism as cause of ß-catenin stabilization by Wnt.
Asunto(s)
Cadherinas/fisiología , Cateninas/fisiología , Glucógeno Sintasa Quinasa 3/metabolismo , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Cuerpos Multivesiculares/metabolismo , Vía de Señalización Wnt , Animales , Cadherinas/metabolismo , Cateninas/metabolismo , Caveolinas/metabolismo , Células HEK293 , Humanos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/análisis , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/análisis , Ratones , Fosforilación , Proteína Wnt3A/metabolismo , Proteína Wnt3A/fisiología , Catenina deltaRESUMEN
Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samplesâ Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-ß signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.