Abstract
Objective The purpose of this work is to study the mechanism of action of Duhuo Jisheng Decoction (DHJSD) in the treatment of osteoporosis based on the methods of bioinformatics and network pharmacology. Methods In this study, the active compounds of each medicinal ingredient of DHJSD and their corresponding targets were obtained from TCMSP database. Osteoporosis was treated as search query in GeneCards, MalaCards, DisGeNET, Therapeutic Target Database (TTD), Comparative Toxicogenomics Database (CTD), and OMIM databases to obtain disease-related genes. The overlapping targets of DHJSD and osteoporosis were identified, and then GO and KEGG enrichment analysis were performed. Cytoscape was employed to construct DHJSD-compounds-target genes-osteoporosis network and protein-protein interaction (PPI) network. CytoHubba was utilized to select the hub genes. The activities of binding of hub genes and key components were confirmed by molecular docking. Results 174 active compounds and their 205 related potential targets were identified in DHJSD for the treatment of osteoporosis, including 10 hub genes (AKT1, ALB, IL6, MAPK3, VEGFA, JUN, CASP3, EGFR, MYC, and EGF). Pathway enrichment analysis of target proteins indicated that osteoclast differentiation, AGE-RAGE signaling pathway in diabetic complications, Wnt signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, JAK-STAT signaling pathway, calcium signaling pathway, and TNF signaling pathway were the specifically major pathways regulated by DHJSD against osteoporosis. Further verification based on molecular docking results showed that the small molecule compounds (Quercetin, Kaempferol, Beta-sitosterol, Beta-carotene, and Formononetin) contained in DHJSD generally have excellent binding affinity to the macromolecular target proteins encoded by the top 10 genes. Conclusion This study reveals the characteristics of multi-component, multi-target, and multi-pathway of DHJSD against osteoporosis and provides novel insights for verifying the mechanism of DHJSD in the treatment of osteoporosis.
Highlights
Osteoporosis is characterized by low bone mass, impaired bone microstructure, increased bone fragility, and susceptibility to fracture and is a systemic bone disease [1]
Osteoporosis-related targets were obtained through retrieving GeneCards [23], MalaCards [24], DisGeNet database [25], erapeutic Target Database (TTD) [26], Comparative Toxicogenomics Database (CTD) [27], and Online Mendelian Inheritance in Man (OMIM) [28] using the keyword “osteoporosis.” GeneCards is a comprehensive, user-friendly database providing information on all annotated and predicted human genes, and we screen out targets with the relevance score ≥10 [23]
A total of 1939 compounds in Duhuo Jisheng Decoction (DHJSD) were retrieved through the TCMSP database, of which 99 were from Du Huo, 46 were from Sang Ji Sheng, 27 were from Qin Jiao, 173 were from Fang Feng, 192 were from Xi Xin, 34 were from Fu Ling, 189 were from Chuan Xiong, 85 from Bai Shao, 147 from Du Zhong 190 from Ren Shen, 280 from Gan Cao, 125 from Dang Gui, 176 from Niu Xi, 76 from Shu Di Huang, and 100 from Rou Gui
Summary
Osteoporosis is characterized by low bone mass, impaired bone microstructure, increased bone fragility, and susceptibility to fracture and is a systemic bone disease [1]. Drug therapies such as bisphosphonates and denosumab are commonly used to treat osteoporosis by inhibiting the development, formation, and survival of osteoclasts [1]. These drugs are effective, high-dose or long-term use may cause serious adverse effects, such as gastrointestinal tolerance, atypical long bone fracture, jaw osteonecrosis, and acute renal failure [1]. Erefore, continuing to search for potential drugs with significant efficacy and high safety has become a consistent hot spot for the treatment of osteoporosis. TCM has been used as a complementary and alternative treatment option for patients with osteoporosis [6]. Systematic reviews and experimental studies have explored the efficacy and safety of TCM prescriptions in the treatment of osteoporosis, including Duhuo Jisheng Decoction (DHJSD), Xianling Gubao capsules, Liuwei Dihuang Decoction, and Erxian Decoction [2, 7,8,9]
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