RESUMEN
UNLABELLED: An isopropanolic extract (iCR) from the rhizomes of Cimicifuga racemosa (black cohosh) is used an alternative in the treatment of menopausal symptoms, and animal studies suggest positive skeletal effects. iCR stimulated osteoblastic OPG protein secretion by 3- to 5-fold as early as 12 h without affecting RANKL expression. The iCR effect, abrogated by the pure estrogen receptor antagonist ICI 182,780, also enhanced ALP activity (4-fold) and osteocalcin expression (3-fold), possibly contributing to the skeletal effects of black cohosh. 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.
Asunto(s)
Cimicifuga/química , Glicoproteínas/metabolismo , Osteoblastos/efectos de los fármacos , Extractos Vegetales/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , 2-Propanol/química , Adulto , Fosfatasa Alcalina/metabolismo , Proteínas Portadoras/genética , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Estradiol/análogos & derivados , Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Femenino , Fulvestrant , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Glicoproteínas/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Menopausia , Osteoblastos/citología , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoprotegerina , Extractos Vegetales/uso terapéutico , Ligando RANK , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor Activador del Factor Nuclear kappa-B , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Progesterona/genética , Receptores del Factor de Necrosis Tumoral/genéticaRESUMEN
Most clinical trials on phytoestrogens detected no significant effects on classic menopausal symptoms. Soy-rich diets positively influence certain aspects (e.g. sleep disturbances and mood swings), but the level of relief is low. Duration of the specific diet before menopause onset predicts the extent of the benefit. Isoflavones exert competitive effects at the estrogen receptor and might interfere with anti-proliferative properties of endocrine anti-cancer therapies. Clinical trials on effects of Actaea racemosa (black cohosh) extracts on menopausal symptoms have yielded more positive results. Two recent studies showed excellent efficacy against classic menopausal complaints and osteoprotective properties, and extracts were deemed safe even when the dosage was increased threefold. Furthermore, several studies suggest that A. racemosa extracts might help control psychic problems typically found during menopausal transition.