Inhibitory effect of Astragalus polysaccharide on osteoporosis in ovariectomized rats by regulating FoxO3a /Wnt signaling pathway.

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.

Inhibitory effect of Astragalus polysaccharide on osteoporosis in ovariectomized rats by regulating FoxO3a /Wnt signaling pathway

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.

Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6.

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.

Expression of Wnt and TGF-ß pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness.

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 samples⋅ 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.