Network pharmacology-based strategy to investigate pharmacological mechanism of Liuwei Dihuang Pill against postmenopausal osteoporosis

Abstract

Postmenopausal osteoporosis (PMOP) has became 1 of most prevalent bone disorders with aging population. Liuwei Dihuang (LWDH) Pill, a classical kidney-tonifying prescription, is extensively used to treat PMOP in China. The aim of this study is to explore the pharmacological mechanisms of LWDH Pill against PMOP via network pharmacological strategy. The active ingredients of LWDH Pill were screened out from the Traditional Chinese Medicine System Pharmacology, Encyclopedia of Traditional Chinese Medicine and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine Databases, and their related target genes were fished in the UniProt database. Simultaneously, the GeneCards and DisGeNET databases were used to identify the target genes of PMOP. Through establishing a protein-protein interaction network, the overlapping genes between LWDH Pill and PMOP were identified to analyze their interactions and the hub target genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to predict the underlying biological processes (BP) and signaling pathways, respectively. A total of 64 active ingredients and 653 related target genes were identified in LWDH Pill, and 292 target genes were closely associated with PMOP. After matching the target genes between LWDH Pill and PMOP, 84 overlapping targets were obtained and considered as therapeutically relevant. Through construction of a protein-protein interaction network, we identified 20 hub target genes including IL6, INS, tumor necrosis factor, AKT1, vascular endothelial growth factor A, IGF1, TP53, IL1B, MMP9, JUN, LEP, CTNNB1, EGF, PTGS2, PPARG, CXCL8, IL10, CCL2, FOS and ESR1. Gene Ontology enrichment analysis suggested that LWDH Pill exerted anti-PMOP effects via regulating multiple BP including cell proliferation and apoptosis, oxidative stress, inflammation and angiogenesis. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed several pathways, such as PI3K-AKT pathway, mitogen-activated protein kinase pathway, hypoxia-inducible factors-1 pathway, tumor necrosis factor pathway, interleukin-17 (IL-17) pathway and FoxO pathway that might be involved in modulating the above BP. Through network pharmacological approach, we investigated the potential therapeutic mechanism of LWDH Pill against postmenopausal osteoporosis in a systemic perspective. These identified multi-targets and multi-pathways provide promising directions for further revealing more exact mechanisms.

Research Progress of Chinese Medicine in Treating Postmenopausal Women with Osteoporosis

“…Early scholars Zou Chongqi [33] treated 60 patients with PMOP with the addition and subtraction of Liuweidihuangwan, with an overall effective rate of more than 85%, and before and after the treatment, the patients' bone mineral density, estrogen, and other indicators were improved compared with the previous treatment. A recent Meta-analysis that included 14 studies from 12 papers also showed [34] that Liuwei Di Huang Wan could improve the treatment efficiency of PMOP patients and also had a role in their pain relief.…”

Mechanisms of action and synergetic formulas of plant-based natural compounds from traditional Chinese medicine for managing osteoporosis: a literature review

“…In terms of TCM formulas for the treatment of OP, LWDHP increases the BMD of femurs and improves the biomechanical capability of the vertebral body in OVX rats, mechanically, it could upregulate Runx2 and Osx expression and augment the number of calcified nodules in OBs by activating canonical Wnt/β-catenin cascade through the increase of Lrp-5 and β-catenin expressions ( 89 ). Bioinformatics analysis also provides potential therapeutic targets of LWDHP against OP such as AKT1, ATF2, and FBXW7 from a systemic perspective ( 90 , 96 ). Qing’e Pill (QEP) inhibits OB ferroptosis and increases the transcription of osteogenesis-related genes, such as BMP2 , Runx2 to increase the number of trabecula and trabecular connections by activating PI3K/AKT pathway and inhibiting ATM Serine/Threonine Kinase expression, thereby exerting a therapeutic role in OVX rats ( 97 ).…”

Consequences of Aging on Bone

“…Moreover, traditional Chinese medicine has a vital role in preventing osteoporosis. Eumoides [403], Epimedium [404], and Liuwei Dihuang pill [405], a classic formula for invigorating kidneys, have been widely used in the treatment of postmenopausal OP for a long time. Qing'e-decoction has also been confirmed to regulate bone metabolism, improve bone quality and delay bone aging, which may be achieved by increasing sex hormones, serum leptin receptor, and leptin receptor [406].…”