Abstract
The lignan-rich fraction (SWR) of Sambucus Williamsii Ramulus, a folk herbal medicine in China for treatment of bone diseases, has previously reported to exert protective effects on bone without exerting uterotrophic effects in ovariectomized (OVX) mice. The aim of the present study was to identify the potential metabolites and the associated metabolic pathways that contribute to the beneficial effects of SWR on bone in vivo. Aged female Sprague Dawley rats (9 months old) were either sham-operated or ovariectomized for 12 weeks, before receiving treatment for another 12 weeks with the following treatment groups (n = 12 each): vehicle (Sham), vehicle (OVX), Premarin (130 μg/kg) or low (57 mg/kg), medium (114 mg/kg), and high (228 mg/kg) doses of SWR. The results showed that SWRH significantly suppressed bone loss, improved bone micro-architecture and increased bone strength on tibia without stimulating uterus weight gain in OVX rats. Premarin exerted similar bone protective effects as SWRH but elicited uterotrophic effects in OVX rats. The metabolic profiles of serum samples were analyzed by using ultra-performance liquid chromatography quadrupole time-of flight mass spectrometry and gas chromatography time-of flight mass spectrometry, and the metabolites that were significantly altered were identified by multivariate statistical analysis. Our study indicated that SWRH effectively restored the changes of 26 metabolites induced by estrogen-deficiency in OVX rats, which related to lipids, amino acids, tryptophan metabolisms, and anti-oxidative system. A subsequent validation showed that the serum level of superoxide dismutase and catalase were indeed up-regulated, while the serotonin level in a tryptophan hydroxylase 1 (TPH1) high expressing cells (rats RBL-2H3 cells) was down regulated after treatment with SWR. The results also suggested that the gut-microbiota may play an important role on the bone protective effects of SWR. The current study provides insight for understanding the unique mechanism of actions of SWR that might be involved in achieving bone protective effects in vivo.
Highlights
Osteoporosis, characterized as the reduction of bone mass and deterioration of bone architecture, is a major cause of morbidity and mortality in the aging population
The present study demonstrated that the lignan-rich fraction from Sambucus Williamsii Ramulus could alter endogenous metabolic pathways in aged ovariectomized rats and such changes might be associated with its bone protective effects
Our outcomes from metabolomics indicated that the levels of both methionine and serine were significantly upregulated in OVX rats in response to treatment with SWRH. These results indicated that SWRH might improve bone mass in OVX rats by restoring the alteration of methionine and serine in homocysteine metabolism induced by estrogendeficiency
Summary
Osteoporosis, characterized as the reduction of bone mass and deterioration of bone architecture, is a major cause of morbidity and mortality in the aging population. Osteoporosis causes more than 8.96 million fractures in the population of age over 50 years in 2000 (Johnell and Kanis, 2006) and up to 50% of women and 20% of men >50 years of age are at risk of fractures (Eastell et al, 2016; Curtis et al, 2017). Metabolic pathways play an important role in age-related bone loss. Several circulating metabolites and proteins have been developed to be biomarkers for identifying the state of bone metabolism that aimed for diagnosis and treatment of bone diseases (Naylor and Eastell, 2012). Identification of metabolites that associated with bone loss will increase our ability to understand the biological mechanism of osteoporosis and to delineate the systematic actions of drug treatment
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