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      Osteoprotective effect of combination therapy of low-dose oestradiol with G15, a specific antagonist of GPR30/GPER in ovariectomy-induced osteoporotic rats

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          Abstract

          Administration of low-dose oestradiol (E2) combining G15, this combination therapy may be an effective supplement of drugs in prevention and treatment for postmenopausal osteoporosis.

          Abstract

          Identified and cloned in 1996 for the first time, G protein-coupled oestrogen receptor (ER) 30 (GPR30/GPER) has been a hot spot in the field of sex hormone research till now. In the present study, we examined the effects of low-dose oestradiol (E2) combined with G15, a specific antagonist of GPR30 on ovariectomy (OVX)-induced osteoporosis in rats. Female Sprague–Dawley (SD) rats undergoing OVX were used to evaluate the osteoprotective effect of the drugs. Administration of E2 [35 μg/kg, intraperitoneally (ip), three times/week) combining G15 (160 μg/kg, ip, three times/week) for 6 weeks was found to have prevented OVX-induced effects, including increase in bone turnover rate, decrease in bone mineral content (BMC) and bone mineral density (BMD), damage of bone structure and the aggravation in biomechanical properties of bone. The therapeutic effect of these two drugs in combination was better than that of E2 alone. Meanwhile, the administration of G15 prevented body weight increase or endometrium proliferation in the rats. In conclusion, administration of low-dose E2 combining G15 had a satisfactory bone protective effect for OVX rats, without significant influence on body weight or the uterus. This combination therapy may be an effective supplement of drugs in prevention and treatment for postmenopausal osteoporosis.

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          The ovariectomized rat model of postmenopausal bone loss.

          Dike Kalu (1991)
          An animal model of postmenopausal bone loss can be defined as a living animal in which spontaneous or induced bone loss due to ovarian hormone deficiency can be studied, and in which the characteristics of the bone loss and its sequalae resemble those found in postmenopausal women in one or more respects. Although in comparison to humans, the skeletal mass of rats remains stable for a protracted period during their lifespan, rats can be ovariectomized to make them sex-hormone deficient, and to stimulate the accelerated loss of bone that occurs in women following menopause. Ovariectomy induced bone loss in the rat and postmenopausal bone loss share many similar characteristics. These include: increased rate of bone turnover with resorption exceeding formation; and initial rapid phase of bone loss followed by a much slower phase; greater loss of cancellous than cortical bone; decreased intestinal absorption of calcium; some protection against bone loss by obesity; and similar skeletal response to therapy with estrogen, tamoxifen, bisphosphonates, parathyroid hormone, calcitonin and exercise. These wide-ranging similarities are strong evidence that the ovariectomized rat bone loss model is suitable for studying problems that are relevant to postmenopausal bone loss.
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            Cloning of a novel receptor expressed in rat prostate and ovary.

            G G Kuiper, E Enmark, M Pelto-Huikko … (1996)
            We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone 29 protein is unique in that it is highly homologous to the rat estrogen receptor (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal ligand-binding domain (55%). Expression of clone 29 in rat tissues was investigated by in situ hybridization and prominent expression was found in prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells of the secretory alveoli, whereas in the ovary the granuloma cells in primary, secondary, and mature follicles showed expression of clone 29. Saturation ligand-binding analysis of in vitro synthesized clone 29 protein revealed a single binding component for 17beta-estradiol (E2) with high affinity (Kd= 0.6 nM). In ligand-competition experiments the binding affinity decreased in the order E2 > diethylstilbestrol > estriol > estrone > 5alpha-androstane-3beta,17beta-diol > testosterone = progesterone = corticosterone = 5alpha-androstane-3alpha,17beta-diol. In cotransfection experiments of Chinese hamster ovary cells with a clone 29 expression vector and an estrogen-regulated reporter gene, maximal stimulation (about 3-fold) of reporter gene activity was found during incubation with 10 nM of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all-trans-retinoic acid, nor 5alpha-androstane-3alpha,I7beta-diol could stimulate reporter gene activity, whereas estrone and 5alpha-androstane-3beta,17beta-diol did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha) from rat uterus.
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              In vivo Effects of a GPR30 Antagonist

              Megan K. Dennis, Ritwik Burai, Chinnasamy Ramesh … (2009)
              Estrogen is central to many physiological processes throughout the human body. We have previously shown that the G protein-coupled receptor GPR30/GPER, in addition to classical nuclear estrogen receptors (ERα/β), activates cellular signaling pathways in response to estrogen. In order to distinguish between the actions of classical estrogen receptors and GPR30, we have previously characterized a selective agonist of GPR30, G-1 (1). To complement the pharmacological properties of G-1, we sought to identify an antagonist of GPR30 that displays similar selectivity against the classical estrogen receptors. Here we describe the identification and characterization of a G-1 analog, G15 (2) that binds to GPR30 with high affinity and acts as an antagonist of estrogen signaling through GPR30. In vivo administration of G15 reveals that GPR30 contributes to both uterine and neurological responses initiated by estrogen. The identification of this antagonist will accelerate the evaluation of the roles of GPR30 in human physiology.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biosci Rep
                Journal ID (iso-abbrev): Biosci. Rep
                Journal ID (hwp): ppbioscirep
                Journal ID (publisher-id): BSR
                Title: Bioscience Reports
                Publisher: Portland Press Ltd.
                ISSN (Print): 0144-8463
                ISSN (Electronic): 1573-4935
                Publication date (Electronic preprint): 3 July 2015
                Publication date (Electronic): 18 August 2015
                Publication date Collection: August 2015
                Volume: 35
                Issue: 4 ( displayID: 4 )
                Electronic Location Identifier: e00239
                Affiliations
                [* ]Department of Orthopedics, Clinical School of Nanjing, Second Military Medical University, Nanjing 210002, China
                [† ]Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China
                [‡ ]Department of Orthopedics, Yangzhou No 1 People's Hospital, Second Clinical School of Yangzhou University, Yangzhou 225000, China
                [§ ]Department of Stomatology, Chongqing Medical University, Chongqing 400016, China
                [∥ ]Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
                Author notes
                [1]

                These authors contributed equally to this work.

                [ 2 ]Correspondence may be addressed to either of these authors (email gangliu3@ 123456126.com or zhaojianning.0207@ 123456163.com ).
                Article
                Publisher ID: e00239
                DOI: 10.1042/BSR20150146
                PMC ID: 4613688
                PubMed ID: 26181370
                SO-VID: c5afdca2-d514-4d21-96aa-f419ec171559
                Copyright © © 2015 Authors
                License:

                This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution Licence 3.0.

                History
                Date received : 3 June 2015
                Date revision received : 3 June 2015
                Date accepted : 16 June 2015
                Page count
                Figures: 7, Tables: 4, References: 21, Pages: 9
                Categories
                Subject: Original Papers
                Subject: Original Paper

                ScienceOpen disciplines: Life sciences
                Keywords: bone,g15,g protein-coupled oestrogen receptor 30 (gpr30/gper),oestradiol (e2),osteoporosis,ovariectomy (ovx)
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: bone, g15, g protein-coupled oestrogen receptor 30 (gpr30/gper), oestradiol (e2), osteoporosis, ovariectomy (ovx)

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