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Title: 8-prenylgenistein, a derivative of genistein, exerted osteoprotective effects without uterotrophic activity
Authors: Zhang, Y
Zhou, L
Ho, MX
Wong, MS 
Issue Date: 2016
Source: ENDO 2016 : The Endocrine Society's 98th Annual Meeting and Expo, Boston, USA, 1-4 April 2016, SUN-356 How to cite?
Abstract: Emerging evidences demonstrated prenylation at C8 position enhanced the biological activities of the flavonoid compounds. Our previous studies reported the in vitro osteogenic effects of 8-prenylgenistein (8PG), an active compound isolated from Erythrina variegata L. possessing osteoprotective effects. Its actions on osteoblastic functions were much stronger than those of genistein in osteoblastic (UMR 106 and MC3T3-E1) cell lines. The present study aimed to study the in vivo osteoprotective effects of 8PG in ovariectomized (OVX) mice as well as to delineate the mechanism of actions involved. The OVX mice were treated with phytoestrogen-free AIN-93M diet containing 8PG (300 & 600 ppm) or its backbone compound genistein (300 ppm) for 6 weeks. Trabecular bone properties were measured by micro-computed tomography (micro-CT). RT-PCR and immunoblotting were performed to study mRNA and protein expression in bone and uterus. In addition, the potential estrogenic effects were determined by in vivo and in vitro approaches. High dose of 8PG significantly improved trabecular bone microarchitecture and increased bone mineral density at the proximal metaphysis of tibia (P < 0.05), while genistein and low dose of 8PG only showed weak effects at this bone site. The trabecular bone mass and most of the micro-structural parameters were significantly ameliorated at the distal metaphysis of femur in OVX mice upon treatment with genistein and both doses of 8PG (P < 0.05). The beneficial effects of 8PG on trabecular bone were confirmed by safranin O staining and the re-constructed 3D micro-CT image. 8PG markedly inhibited the ovariectomy-induced elevation of bone mRNA expressions of RANKL/OPG, ALP, type 1 collagen and estrogen receptor alpha (ER-α) in mice. In contrast, genistein further increased the OVX-induced ER-α expression in bone of OVX mice. More importantly, the uterus index was increased in genistein-treated group, but not in 8PG-treated groups. Gene expression analysis showed that genistein up-regulated the mRNA expression of estrogen-sensitive genes such as PR and ER-α, while 8PG significantly down-regulated the ER-α mRNA expression and did not influence PR expression in the uterus of OVX mice. Competitive binding assay showed that the ability of genistein and 8PG to bind ER-α were comparable, while the binding affinity of 8PG to ER-β was lower than that of genistein. Taken together, this study demonstrated the 8PG improved bone properties in OVX mice without exerting uterotrophic effects. Future study is needed to characterize the molecular mechanisms of 8PG and genistein that account for their differential actions in bone and reproductive tissues.
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