High-throughput metabolomics investigates anti-osteoporosis activity of oleanolic acid via regulating metabolic networks using ultra-performance liquid chromatography coupled with mass spectrometry

Background: Osteoporosis has brought about heavy socio-economic burden in the morbidity and medical expenses associated with osteoporosis treatment and various restrictions on behavior of their social roles. Oleanolic acid (OA) is an anti-osteoporosis natural product, but molecular mechanisms of therapeutic effect are not still well known. Purpose: In this study, we explore anti-osteoporosis activity of oleanolic acid and predict the underlying mechanisms by metabolomics strategy. Methods: SD rats were intraperitoneal injection with prednison for once to establish osteoporosis model. Using metabolomics strategy based on ultra-performance liquid chromatography coupled with quadrupole time-offlight/ mass spectrometry (UPLC-TOF/MS), serum samples of 24 rats were analyzed to seek differential metabolites and pathway associated with OA treatment of osteoporosis. In addition, the effect of OA on osteoporosis rats was also evaluated by clinical biochemistry indicators and bone density analysis. Results: Clinical biochemistry indicators and bone density of lumbar and femur were reversed by OA treatment. A total of 25 potential biomarkers were identified in the rats model of glucocorticoid-induced osteoporosis, and oleanolic acid have a regulatory effect on 17 of them that related to some vital metabolic pathway such as linoleic acid metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis as well as cysteine and methionine metabolism. The ingenuity pathway analysis (IPA) platform is applied to further understanding the relationship between metabolic changes and therapeutic effect of OA, which the disordered state carbohydrate metabolism, molecular transport and lipid metabolism in glucocorticoid-induced osteoporosis rats are mainly ameliorated by oleanolic acid. Conclusion: Metabolomics provides a novel method to investigate the anti-osteoporosis effects of OA and probe into the potential mechanisms, and will contributes to the development of new drugs.