Abstract
Post-menopausal osteoporosis (PMOP) is associated with estrogen deficiency and worldwide, is becoming increasingly more prevalent in aging women. Various anti-PMOP drugs have been developed to reduce the burden of PMOP; generally, these drugs are efficacious, but with some adverse side effects. Tubson-2 decoction (TBD), a popular traditional Mongolian medicine, has been used to treat PMOP for centuries. However, the precise mechanisms underlying the action of TBD on PMOP have yet to be fully elucidated. Herein, we combined network pharmacology with untargeted metabolomics to identify the key targets and metabolic pathways associated with the interventional effects of TBD on ovariectomized (OVX) rats. Furthermore, we investigated the bone histomorphometry of eight different groups of rats to evaluate the therapeutic effect of TBD. First, we established a TBD-target/PMOP network via network pharmacology; this network identified three key protein targets—vitamin D receptor (VDR), cytochrome P450 19A1 (CYP19A1), and 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1). Morphological analysis showed that severe impairment of the bone micro-architecture in OVX rats could be improved by TBD administration. The TBD-treated rats had a significantly lower bone surface-to-tissue volume (BS/TV) and a significantly smaller trabecular separation (Tb·Sp.) (P<0.05) than the OVX rats; in contrast, bone volume fraction (BVF), trabecular thickness (Tb·Th.), trabecular number (Tb·N.), and bone mineral density (BMD) were significantly higher in the TBD-treated rats (P<0.05). Multivariate and univariate analysis showed that OVX resulted in significant alterations in the concentrations of 105 metabolites and 11 metabolic pathways (P<0.05); in addition, 26 potential biomarkers were identified to investigate the progression of PMOP. Network pharmacology showed that major alterations in vitamin B6 metabolism were associated with the VDR target. Next, we validated the three crucial targets (VDR [P<0.01], HSD11B1 [P<0.01], and CYP19A1 [P<0.05]) by enzyme-linked immunosorbent assays (ELISAs) and demonstrated that the levels of these targets were elevated in the OVX group but reduced in the TBD-treatment group. Collectively, our results suggest that the interventional effects of TBD on OVX rats are likely to be associated with the down regulation of VDR. Our findings enhance our molecular understanding of the interventional effects of TBD on PMOP and will allow us to develop further TBD studies.
Highlights
Osteoporosis is a systemic bone disease that results in alterations in the microscopic architecture of the bone and a reduction in bone mass (Zou et al, 2020); collectively, these effects result in an impairment of bone quality
We found that the OVX group showed significant changes in both bone mineral density (BMD) and trabecular microarchitecture
Analysis revealed that there was a significant reduction in Tb·N. (P=0.003), Bone volume fraction (BVF) (P=0.011), BMD (P=0.008), and bone surface to tissue volume (BS/TV) (P=0.001), along with a significant increase in Tb·Sp. (P=0.000) in the OVX group (Figures 3A–F)
Summary
Osteoporosis is a systemic bone disease that results in alterations in the microscopic architecture of the bone and a reduction in bone mass (Zou et al, 2020); collectively, these effects result in an impairment of bone quality. Many researchers have highlighted the fact that many herbs, and prescriptions created from these herbs, can exert and estrogen-like action, including Eucommia ulmoides Oliver (EC) (Zhang et al, 2012), Epimedium brevicornu Maxim (Liu H. et al, 2018), Achyranthes bidentata (Zhang M. et al, 2018), and Echinops latifolius Tausch (ELT) (Wang et al, 2020) Considering that these herbs, and their prescriptions, are known to have good anti-osteoporosis effects, it follows that TCM (Li et al, 2018), and other ethnic medicines, may represent a natural drug resource for screening new drugs for the treatment of PMOP
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