Isopropanolic Extract of Black Cohosh Stimulates Osteoprotegerin Production by Human Osteoblasts

Department of Obstetrics and Gynecology, Georg-August-University of Göttingen, Göttingen, Germany.
Journal of Bone and Mineral Research (Impact Factor: 6.83). 11/2005; 20(11):2036-43. DOI: 10.1359/JBMR.050716
Source: PubMed


Introduction: Despite its positive effects on the skeleton, estrogen replacement therapy is no longer recommended as first-line therapy for the prevention and treatment of postmenopausal osteoporosis because it increases cardiovascular, thromboembolic, and breast cancer risk. Recently, herbal therapeutics such as an isopropanolic extract (iCR) from the rhizomes of Cimicifuga (=Actaea) racemosa (black cohosh) are gaining interest as an alternative in the treatment of menopausal symptoms. Whereas animal studies in rats suggest positive skeletal effects, the mechanism of its actions on bone cells remain unclear. RANKL is essential for osteoclast formation and activation, while osteoprotegerin (OPG) neutralizes RANKL. Materials and Methods: In this study, we assessed the effects of iCR on OPG and RANKL mRNA steady-state levels by semiquantitative RT-PCR and on protein production by an ELISA system in human osteoblasts (hOBs). Results: Under serum-free conditions, treatment with iCR increased OPG mRNA levels and protein secretion of hOBs by 2- to 3-fold in a dose-dependent manner, with a maximum effect at a 10(6)-fold dilution of iCR (p < 0.001) after 24-48 h. Time-course experiments indicated a stimulatory effect of iCR on osteoblastic OPG protein secretion by 3- to 5-fold (p < 0.001) as early as 12 h, whereas RANKL expression was very low and was not found to be modulated by iCR. Of note, the stimulatory effect of iCR on OPG production was abrogated by the pure estrogen receptor antagonist ICI 182,780. Moreover, iCR enhanced two osteoblastic differentiation markers, bone-specific alkaline phosphatase activity and osteocalcin expression, by up to 4- and 3-fold, respectively (p < 0.001). Conclusions: Our data suggest that iCR enhances differentiation and increases the OPG-to-RANKL ratio of normal human osteoblasts. These effects may contribute to the positive skeletal effects of black cohosh.

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Available from: Carsten Gründker, Sep 25, 2014
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    • "When drug therapy was applied, the bone turnover rate was inhibited and the bone formation rate decreased accordingly, so no statistical variations in the bone formation markers were found between the four groups. In addition, an in vitro study reported that Remifemin promoted the production of osteoprotegerin in osteoblasts and increased the serum concentration of OC and bone alkaline phosphatase, both of which could promote bone formation [46]. However, further studies on the association between Remifemin and bone formation are needed. "
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    ABSTRACT: This study aims to evaluate the effects of Remifemin (isopropanolic extract of Cimicifuga Racemosa) on postmenopausal osteoporosis. 120 female Sprague-Dawley rats were randomly assigned to four groups: sham surgery with vehicle, ovariectomy with vehicle, ovariectomy with estradiol valerate, or ovariectomy with Remifemin. Daily oral administrations of the vehicle, estradiol valerate, or Remifemin began 2 weeks after surgery and lasted to 4, 8, or 12 weeks. Ten rats in each group were sacrificed at each timestep with assessment of bone mineral density, trabecular bone structure, and biomechanical parameters of the femur and lumbar vertebra. Bone turnover markers were evaluated 12 weeks after surgery. Both drugs prevented bone density loss in the distal end of the femur and preserved the trabecular bone structure in both the lumbar vertebra and distal end of the femur following ovariectomy. Both drugs protected bone stiffness at the tested regions and reduced bone reabsorption in ovariectomized rats. The preventive effects of Remifemin against bone-loss can rival those of estradiol valerate if treatment duration is adequately extended. In conclusion, Remifemin may demonstrate equivalent effects to estradiol valerate in terms of preventing postmenopausal osteoporosis.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "not estrogenic ) of hormone dependent or independent breast or prostate cancer cell lines, but does inhibit proliferation (antiestrogenic) through the induction of apoptosis (Dixon-Shanies and Shaikh, 1999, Amato et al. 2002, Zierau et al. 2002, Lupu et al. 2003, Bodinet and Freudenstein, 2004, Hostanska et al. 2004a, Jarry et al. 2005, Bodinet and Freudenstein, 2002, Hostanska et al. 2004b, Hostanska et al. 2005). However, like estrogen, BCE induces osteoprotegerin (OPG, a bone marker), progesterone receptor, and ERα in human osteoblast cells, and BCE upregulation of OPG is inhibited by the estrogen receptor antagonist ICI 182,780, implying an estrogenic mechanism (Viereck et al. 2005). "
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    ABSTRACT: The Women’s Health Initiative found that combination estrogen and progesterone hormone replacement therapy increases breast cancer and cardiovascular disease risk, which compelled many women to seek herbal alternatives such as black cohosh extract (BCE) to relieve their menopausal symptoms. While several clinical trials document the efficacy of BCE in alleviating menopausal symptoms, preclinical studies to determine how BCE works have yielded conflicting results. Part of this is because there is not a universally accepted method to standardize the dose of black cohosh triterpenes, the presumed active ingredients in the extract. Although the mechanism by which BCE relieves symptoms is unknown, several hypotheses have been proposed: it acts 1) as a selective estrogen receptor modulator, 2) through serotonergic pathways, 3) as an antioxidant, or 4) on inflammatory pathways. We found that while the most prominent triterpene in BCE, 23-epi- 26-deoxyactein, suppresses cytokine-induced nitric oxide production in brain microglial cells, the whole BCE extract actually enhanced this pathway. A variety of activities have been reported for black cohosh and its compounds, but the absorption and tissue distribution of these compounds is unknown.
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    • "By contrast, the role of the ER-b in tumor cell biology of breast cancer is less clear [1]. Our data clearly show that 17b-estradiol suppression of OPG is dose-dependent and specifically mediated through the ER, two major criteria for a physiologically relevant response [7] [17] [19]. Our data also indicate that even very low concentrations of 17b-estradiol are capable of suppressing OPG production by breast cancer cells. "
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    ABSTRACT: Estrogen regulates various cytokines and growth factors in estrogen receptor (ER)-positive human breast cancer. Receptor activator of NF-kappaB ligand (RANKL) is an essential cytokine for osteoclasts, whereas osteoprotegerin (OPG) is a soluble inhibitor for RANKL. We analyzed the regulation of the RANKL/OPG system by estrogens and androgens in the ER-positive breast cancer cell line MCF-7 and the ER-negative breast cancer cell line MDA-MB-231. In MCF-7 cells, which predominantly express ER-alpha, 17beta-estradiol and testosterone dose-dependently decreased OPG mRNA levels and protein secretion by 70 and 65%, respectively (p<0.0001 by ANOVA). The inhibition of OPG production by 17beta-estradiol and testosterone was specifically prevented by the pure anti-estrogen ICI 182,780, and the testosterone effect was prevented by an aromatase inhibitor. In conclusion, 17beta-estradiol suppressed OPG production by human breast cancer cell lines in a dose-dependent and specific manner, indicating that the RANKL/OPG cytokine system is an estrogen-responsive target in breast cancer.
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