The Underlying Mechanism of Chinese Herb of Regulating Marrow in the Treatment of  Osteonecrosis of the Femoral Head Based on Network Pharmacology and Molecular Docking

doi:10.21203/rs.3.rs-699020/v1

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The Underlying Mechanism of Chinese Herb of Regulating Marrow in the Treatment of Osteonecrosis of the Femoral Head Based on Network Pharmacology and Molecular Docking

https://doi.org/10.21203/rs.3.rs-699020/v1

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Background

The lesion of marrow is a crucial factor in orthopedic diseases, which is recognized by orthopedics-traumatology expert from "Zhe-School of Chinese Medicine". The Chinese herbs of regulating marrow has been widely used to treat osteonecrosis of the femoral head (ONFH) in China, while the interaction mechanisms were still elucidated. Thus, we conducted this study to explore the underlying mechanism of the five highest-frequency Chinese herbs of regulating marrow(HF-CHRM) in the treatment of ONFH with the aid of network pharmacology(NP) and molecular docking(MD).

Methods

The active components and potential targets of HF-CHRM were obtained through several online databases, such as Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), UniProt database. The gene targets related to ONFH were collected with the help of the OMIM and GeneCards disease-related databases. The "drug- component-target-disease" network and protein-protein interaction(PPI) network of the drug and disease intersecting targets were constructed by using Cytoscape software and the STRING database. R software was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The MD of critical components and targets was carried out using Autodock Vina and Pymol to validate the binding affinity.

Results

A total of 54 active components, 1074 drug targets and 195 gene targets were obtained. There were 1219 ONFH related targets. 39 drug and disease intersection targets(representative genes: IL6, TP53, VEGFA, ESR1, IL1B) were obtained and considered potential therapeutic targets. 1619 items were obtained by the GO enrichment analysis, including 1517 biological processes, 10 cellular components and 92 molecular functions, which is mainly related to angiogenesis, bone and lipid metabolism and inflammatory reaction. The KEGG pathway enrichment analysis revealed 119 pathways, including AGE-RAGE signaling pathway, PI3K-Akt signaling pathway and IL-17 signaling pathway. MD results showed that quercetin, wogonin, and kaempferol active components had good affinity with IL6, TP53, and VEGFA core proteins.

Conclusion

The HF-CHRM can treat ONFH by multi-component, multi-target, and multi-pathway comprehensive action.

Bioinformatics

Chinese herbs of regulating marrow

osteonecrosis of the femoral head

network pharmacology

molecular docking

Osteonecrosis of the femoral head(ONFH) is a chronic progressive disease with a higher incidence and younger age of onset in male compared with their female counterparts(1). The first large-scale non-traumatic osteonecrosis epidemiological survey showed that an estimated 8.12 million people suffer from it, and the affected population is the people in young and middle-aged and the early and middle stages of the disease(2). However, untreated ONFH will develop into hip osteoarthritis, which induces pain, the loss of joint function and ability to walk, and results in a reduced quality of life. Total hip arthroplasty (THA) is recognized as an effective treatment for ONFH(3). Nevertheless, the prosthesis has a certain longevity. For patients with Ⅰ - Ⅱ and Ⅲ A stage of the Association Research Circulation Osseous (ARCO) or mild presenting symptoms and young age, they may experience multiple revision in the later period of THA(3). Therefore, hip-preserving treatments should be actively carried out for such patients.

The theoretical system of "myeloid bone disease(MBD)" was proposed by our team on the basis of the classical theory of Traditional Chinese Medicine(TCM), "Kidney dominates bone", combined with a series of theoretical, basic and clinical research, which mainly refers to bone and joint diseases caused by the dysfunction of stem cells and its microenvironment. The interventions targeted such diseases are to use the "medullary regulation" method, which can be divided into two kinds, namely, “endogenous marrow regulation” and “exogenous marrow filling”(4). The former mainly refers to the use of Chinese herbs of regulating marrow(CHRM) to mobilize stem cell migration and restore bone metabolism homeostasis, delay disease progression. ONFH is called “gu shi” or“gu wei” in TCM and is an important branch in MBD. Previous studies(5, 6) have stated that CHRM can play a positive role in this disease, but its specific pharmacological effects have not been elucidated.

Network pharmacology of TCM and molecular docking(MD) integrates multidisciplinary technology, which can systematic analyze the multi-target molecular mechanism of drug therapy(7). Liu(8) performed the statistical analysis on the herbs used by the ancients to treat MBD and obtained the use frequency. In this paper, we explored the mechanism of the five highest-frequency Chinese herbs of regulating marrow(HF-CHRM)(8), i.e., Radix rehmanniae praeparata(shu di-huang, SD), Radix achyranthis bidentatae(niu xi, NX), Poria cocos(fu ling, FL), Cistanche deserticola(rou cong-rong, RCR), Semen cuscutae(tu si-zi, TSZ), in the treatment of ONFH to provide some new ideas for the treatment of bone disease in TCM.

2.1. Screening of the potentially compounds and targets in HF-CHRM.

All compounds of HF-CHRM were obtained by searching herb names in the Traditional Chinese Medicine Systems Pharmacology database and analysis platform (TCMSP, https://tcmspw.com/index.php, Ver.2.3)(9). The active components of HF-CHRM were screened based on two key index of absorption, distribution, metabolism, and excretion (ADME) parameters, namely oral bioavailability (OB) and drug-likeness (DL). OB ≥ 30%, and DL ≥ 0.18 were set as threshold for active compounds obtaining. Besides, the potential targets was retrieved from the TCMSP database, verifed using the UniProt protein database (https://www.uniprot.org/)(10), and converted into their corresponding gene names.

2.2. Collection of ONFH related Targets.

Here, the targets related to the ONFH wereacquired by retrieving two databases: GeneCards (https://www.genecards.org/)(11) and OMIM (http://www.ncbi.nlm.nih.gov/omim)(12). All of the collected targets were merged and had deleted duplicates of it to find the unique items and establish the target database. The targets of active components in HF-CHRM and the disease related targets were mapped by the Venn Diagram data package, in which of the intersection was reputed to the prediction targets of herbs in treating ONFH.

2.3. Construction of the Herbs‑Active Components‑Targets-Disease Network.

The data obtained in the above process were used to construct the herbs‑active components‑targets-disease network of HF-CHRM in the treating ONFH through the Cytoscape 3.8.0 software, with “herb” being set as a triangle, “active components” being set as an equilateral hexagon, “target” being set as a diamond, an“disease” being set as an oval. The cytoHubba plugin was employed to calculate and rank the degree of all nodes.

2.4. Construction of the Protein–Protein Interaction (PPI) network.

The intersection targets was uploaded to the STRING database(http://string-db.org/)(13) to obtain the PPI network and data, in which the organism parameter was limited to“Homo sapiens”, the interaction confidence score was set as greater than 0.400, and the isolated proteins was hidden in the map. The network data from the STRING database is imported into Cytoscape to get the core targets that scores of betweenness centrality (BC), closeness centrality (CC), eigenvector centrality(EC), and degree centrality (DC) are higher than the median value.

2.5. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Enrichment Analysis.

The “cluster profile” package in R software version 4.0.5 was used to process the GO enrichment analysis and the KEGG pathway analysis, which was visualized by using GraphPad Prism 8 software. Besides, the species type was “Homo sapiens” and the statistical significance threshold of enrichment analysis was P ≤ 0.05. The main active components, the ONFH key targets, and the vital signal pathways were introduced into Cytoscape to construct the network of main active components-key targets-core signal pathways.

2.6. Construction of Components-Targets-Signal Pathways Network.

The data from KEGG pathway enrichment analysis were introduced into Cytoscape to construct the Components-Targets-Signal Pathways network.

2.7. Molecular Docking(MD) Prediction.

Three active components with the highest degree value were docked with the top three targets of the degree. The three-dimensional (3D) protein structures were downloaded from the RCSB PDB database (https://www.rcsb.org/)(14), removed from water molecules by PyMOL 2.4.0, introduced into AutoDockTools 1.5.6 for dehydration, hydrogenation, as well as calculating the charges, and used it as receptors. The 2D structures of the compounds were downloaded from the Pubchem(https://pubchem.ncbi.nlm.nih.gov/), optimized to minimum energy, and transformed into PDB format with the assistance of ChemBio 3D Ultra 14.0 software. AutoDock Vina 1.1.2 was run for MD. The 3D structures conformation with the lowest binding energies and produced by the docking of the component of the highest degree with the top targets of the degree, which was visualized in PyMOL.

2.8 Statistical analysis.

The data were analyzed with R Package and Cytoscape 3.61 software. P < 0.05 was considered as a statistically significant value.

3.1. Active Components and Potential Targets of HF-CHRM.

54 potential compounds in HF-CHRM were retrieved from the TCMSP database through screening by ADME parameters, in which 2, 20, 15, 6, and 11 compounds were originated from SD, NX, FL, RCR, and TSZ. Meanwhile, 195 target genes were acquired after deleting repetitive values. There were 11 intersecting targets of the five HF-CHRM (Fig. 1).

3.2. Prediction results of HF-CHRM targets in treating ONFH.

129 and 1110 targets related to ONFH were obtained respectively through the keywords of “osteonecrosis of the femoral head” in the GeneCards and OMIM databases. A total of 1219 ONFH disease targets were pick up by combining and eliminating duplicates of the above targets. Afterwards, the mapping was carried out between compound and disease targets. As a result, 39 targets were identifed (Fig. 2).

3.3. Herbs‑Active Components‑Targets-Disease Network Analysis.

The drug and disease intersecting targets and corresponding components were imported into the Cytoscape software to construct herbs‑active components‑targets-disease network, involving 60 nodes (including 5 herbs, 15 compounds, 39 genes, and 1 disease) and 335 edges. The node size was proportional to its degree value(Fig. 3). According to the degree values, the order is NX, TSZ, RCR, FL and SD from large to small. The top three degree values of active components and targets were MOL000098, MOL000173, and MOL000422, AR, ESR1, and PPARG.

3.4. Construction of the Protein–Protein Interaction (PPI) network.

With the String database, PPI network was established(Fig. 4), and the correlative data were gathered. Cytoscape software was employed to perform topological analysis, which was visualized by GraphPad Prism 8 software. This network consisted of 37 nodes and 338 edges, of which the average degree was 18.27. Based on the median DC, CC, BC,and EC values, the selected target genes were listed in Fig. 5. Among them, the

top five target proteins were interleukin 6(IL6), tumor protein 53 (TP53), vascular endothelial growth factor A (VEGFA), and Estrogen Receptor 1 (ESR1), which were considered to play a remarkable role in the PPI network.

3.5. GO and KEGG Pathway Enrichment Analysis.

A total of 1619 GO terms were enriched, covering BP, CC, and MF, of which the each top 10 are shown with barplot in Fig. 6. The biological processes mainly involve in epithelial cell proliferation, drug response, and nutrient levels response. The top three cellular components include serine/threonine protein kinase complex, protein kinase complex, and transferase complex. Furthermore, the main molecular functions are cytokine activity, cytokine receptor binding, and serine hydrolase activity. Moreover, a total of 119 KEGG pathways were significantly enriched (P < 0.05). The top 20 are listed in Fig. 7, which mainly contain advanced glycation endproduct- advanced glycation endproduct receptor (AGE − RAGE) signaling pathway, phosphatidylinositol 3-kinase-Akt (PI3K − Akt) signaling pathway, and interleukin-17 (IL-17) signaling pathway.

3.6. Construction of Components-Targets-Signal Pathways Network.

The data fromKEGG pathway enrichment analysis were input Cytoscape software to construct the Components-Targets-Signal Pathways network(Fig.8). The larger the nodes, the moresignificant the impact. It ispredicted that quercetin,wogonin, and kaempferol are important components in theintervention of ONFH.

Table 1: The binding energies of core active compounds and core proteins.

Core component	Source of herbal medicines	Target	PDB ID	Binding energy (kcal/mol)
Quercetin	NX, RCR, TSZ	IL6	1ALU	-6.9
		TP53	1GZH	-7.3
		VEGFA	3S1K	-7.8
Wogonin	NX	IL6	1ALU	-6.4
		TP53	1GZH	-7.7
		VEGFA	3S1K	-7.1
Kaempferol	NX	IL6	1ALU	-6.9
		TP53	1GZH	-7.7
		VEGFA	3S1K	-7.6

3.7. Docking Results.

Classically, the binding energieswere less than −5 kcal/mol, which indicats that the drug and the target protein had goodbinding affinity(15). The MD results showed that the components(quercetin, wogonin, and kaempferol) regarded as ligand and the protein(1ALU, 1GZH, and 3S1K) regarded as receptor had a certain binding activity(Table 1). The docking pattern of quercetin with 1ALU protein and 3S1K protein were shown in Fig. 9. The results showed that quercetin formshydrogen bonds with amino acid residues of ARG-179 and GLN-175 in 1ALU and of ASP-63 and GLU-64 in 3S1K.

The TCM theory of " Kidney dominates bone" put forward the function of marrow. The significance of marrow on orthopedic diseases was underlined by our team that summarized other classical TCM theories, introduced the theory of "myeloid bone diseases", and clarified that stem cells are the existing form of marrow of TCM at the cellular level. The etiology and pathogenesis of ONFH in TCM can be attributed to the dysfunction marrow caused by kidney deficiency, the imbalance of Yin and Yang, and the dystrophy of bone(4). The modern medical etiology and pathogenesis can be summarized as the lack of blood supply to the femoral head, which resulted in the death of bone cells in the area, abnormal bone metabolism, and damage to the trabecular structure, which in turn led to microfractures and eventually caused the femoral head to collapse and change shape(16). In the above process, bone formation and bone resorption phases coexist. Therefore, for ONFH treatment, its repairing effect should be strengthened, which can start from two aspects of bolstering angiogenesis and osteogenesis. CHRM is an effective measure in promoting bone repair and preventing or delaying the progression of ONFH(17). Consequently, it is of great significance to illuminate the specific action mechanism of CHRM in the treatment of bone and joint disease.

Through network pharmacology, it was screened out 54 active components of HF-CHRM, 1219 targets related to ONFH, and 39 targets of intersecting diseas and drug in this study. The top 3 key components were obtained, namely quercetin, wogonin, and kaempferol, by performing the topological analysis of the herbs-active components-targets-disease network. Quercetin is one of the natural polyphenols, which widely exists in various plants and was consumed worldwide(18). It has multiple pharmacological effects reported by many studies, such as protecting the bone, reduceing blood glucose, blood pressure, and lipid, and immunomodulatory, anti-inflammatory, and antioxidation activities(19–21). Wogonin, a compound extracted from the Scutellaria baicalensis plant, exhibits high anti-inflammatory and antioxidative properties, which is achieved reduce expression of transforming growth factor β1 (TGF-β1), high temperature receptor A1 (HTRA1), matrix metalloprotease 13 (MMP-13) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)(22, 23). Moreover, kaempferol have a wide range of pharmacological and biological activities, which mainly include cardioprotective, anxiolytic, anti-allergic, anti-cancer, anti-microbial, anti-hyperlipidemic, anti-oxidative, anti-inflammatory and anti-osteoporotic effects(24–26). Trivedi et al.(27) investigated the anti-osteoclastogenic role of kaempferol that can markedly attenuate adipocyte formation and shows lower serum ALP (bone turnover marker) and higher bone mineral density (BMD) in the trabecular regions (proximal tibia, femur neck, and vertebrae). In summary, most of these core components exhibit beneficial effects on bone metabolism through anti-inflammatory, antioxidant, and anti-hyperlipidemic. Interestingly, the research results suggest that NX is a key herb for the treatment of ONFH with HF-CHRM, which does not correspond to the frequency of use. We speculate that NX may be used less frequently in such MBD such as knee osteoarthritis and osteoporosis.

It is concluded that IL6, TP53, and VEGFA targets play a central role in HF-CHRM treatment of ONFH. IL6 and P53, as representative proteins of inflammation and tumors in the body, are closely related to osteogenesis and osteoclast(28, 29). It was reported that IL6 can regulate the role and activity of various immune cells, promote angiogenesis, and induce the process of bone remodeling(30, 31). TP53, the most frequently altered gene in human tumors, was associated with adverse prognosis in many sporadic cancers, which regulates cell cycle arrest, apoptosis, senescence and DNA repair(32, 33). VEGFA can promote the proliferation and migration of vascular endothelial cells to induce angiogenesis. Besides, some studies(34, 35) have confirmed that it has an important role in the formation of subchondral bone.

The enrichment analysis of the GO and KEGG pathways were undertaken to predict the treatment mechanism. The results of above analysis demonstrate that the targets of HF-CHRM was related to biological response processes of angiogenesis, bone and lipid metabolism, and inflammation. Moreover, KEGG enrichment analysis showed that the key targets were mainly concentrated in the AGE-RAGE signal pathway. Studies(36, 37) have shown that the interaction between AGE and RAGE can produce a series of increase of inflammation and oxidation, causing vascular endothelial damage. At the same time, it can activate the expression NF-κB and TNF-α, diminish osteogenic, bring about osteoclastogenesis increase. The HF-CHRM participate in the regulation of a variety of response processes to work.

What's more, MD results showed that the ligand of the degree top 3 components of HF-CHRM had a strong binding activity with the repector of the degree top 3 components of ONFH, of which the conformations were stable. The HF-CMRM is effective and solid therapeutic role.

However, there are certain limitations in this study. Firstly, the usage frequency of CHRM in our research was formed by the summary statistics of marrow-regulating prescriptions of medical specialists of the past dynasties, which mainly reflects the academic thought of marrow-regulating the ancient orthopaedic specialists. In the later period, the modern usage of marrow-regulating prescriptions will be summarized to obtain experience applied with contemporary orthopedic doctors. And both differences were analysed to derive a better usage regularity of the CHRM. Then, we are unable to perform basic scientific researches and clinical trials to validate the results in a short time.

At present, the main accepted treatment principle is to delay or avoid THA for the early and mid-term ONFH. Correspondingly, there are two major measures of surgery and conservative treatment. The TCM plays an indispensable role,as an important part of conservative treatment, which can not only be combined with modern biological agents, such as PRP, stem cells, etc. to enhance the treatment effect, but also used in conjunction with hip-preserving surgery to improve the success rate of hip-preserving treatments(38). In this study, the mechanism of five HF-CHRM in treating this disease was elucidated through the method of network pharmacology, which confirmed herbs become operative through multitarget, multipathway and comprehensive combined action. Our study results show that various active components of five HF-CHRM, such as quercetin, wogonin, and kaempferol, can act on main targets, involving IL6, TP53, VEGFA, to regulate many biological proceses, achieve ultimately therapeutic outcome through AGE-RAGE, PI3K-AKT, and IL-17 pathways. The above results provides some new research ideas for for the treatment of bone disease in TCM.

ONFH Osteonecrosis of the femoral head

ARCO Association Research Circulation Osseous

THA hip arthroplasty

ARCO Association Research Circulation Osseous

MBD myeloid bone disease

TCM Traditional Chinese Medicine

CHRM Chinese herbs of regulating marrow

HF-CHRM highest-frequency Chinese herbs of regulating marrow

SD shu di-huang

NX niu xi

FL fu ling

RCR rou cong-rong

TSZ tu si-zi

MD molecular docking

TCMSP Traditional Chinese Medicine Systems Pharmacology database and analysis platform

ADME Absorption, distribution, metabolism, and excretion

DL Drug-likeness

OB oral bioavailability

PPI Protein–Protein Interaction

BC betweenness centrality

CC closeness centrality

EC eigenvector centrality

DC degree centrality

3D Three-dimensional

BP Biological process

GO Gene ontology

KEGG Kyoto encyclopedia of genes and genomes

Ethics approval and consent to participate

No applicable.

Consent for publication

No applicable.

Availability of data and materials

The data used in the study are available upon request to the corresponding author.

Competing interests

The authors declare no conflicts of interest.

Funding

This project was supported by the National Natural Science Foundation of China (No.81873325).

Authors' contributions

WXJ and WR drafted the manuscript. XT and LSJ performed the data analysis and prepared the figures and tables. JHT and LSJ corrected the manuscript. TPJ and LSJ conceived and designed the study. All authors proofread and approved the final manuscript.

Acknowledgements

No applicable.

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The Underlying Mechanism of Chinese Herb of Regulating Marrow in the Treatment of Osteonecrosis of the Femoral Head Based on Network Pharmacology and Molecular Docking

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Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials And Methods

2.1. Screening of the potentially compounds and targets in HF-CHRM.

2.2. Collection of ONFH related Targets.

2.3. Construction of the Herbs‑Active Components‑Targets-Disease Network.

2.4. Construction of the Protein–Protein Interaction (PPI) network.

2.5. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Enrichment Analysis.

2.6. Construction of Components-Targets-Signal Pathways Network.

2.7. Molecular Docking(MD) Prediction.

2.8 Statistical analysis.

3. Results

3.1. Active Components and Potential Targets of HF-CHRM.

3.2. Prediction results of HF-CHRM targets in treating ONFH.

3.3. Herbs‑Active Components‑Targets-Disease Network Analysis.

3.4. Construction of the Protein–Protein Interaction (PPI) network.

3.5. GO and KEGG Pathway Enrichment Analysis.

3.6. Construction of Components-Targets-Signal Pathways Network.

4. Discussion

5. Conclusions

Abbreviations

Declarations

References

Status:

Version 1