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Comparative transcriptomics and network pharmacology analysis to identify the potential mechanism of celastrol against osteoarthritis

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Abstract

Introduction

Celastrol is a promising therapeutic agent for the treatment of osteoarthritis (OA). However, the mechanism of action of celastrol is unclear. This study was aiming to identify the potential function of celastrol on OA and determine its underlying mechanism.

Method

Celastrol targets were collected from web database searches and literature review, while pathogenic OA targets were obtained from Online Mendelian Inheritance in Man (OMIM) and GeneCards databases. Transcriptomics data was sequenced using an Illumina HiSeq 4000 platform. Celastrol-OA overlapping genes were then identified followed by prediction of the potential function and signaling pathways associated with celastrol using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A celastrol-target network was constructed to identify the candidate core targets of celastrol. The predictions were then validated by performing molecular docking and molecular dynamics simulation studies.

Results

In total, 96 genes were identified as the putative celastrol targets for treatment of OA. These genes were possibly involved in cell phenotype changes including response to lipopolysaccharide and oxidative stress as well as in cell apoptosis and aging. The genes also induced the mTOR pathway and AGE-RAGE signaling pathway at the intracellular level. Additionally, results indicated that 13 core targets including mTOR, TP53, MMP9, EGFR, CCND1, MAPK1, STAT3, VEGFA, CASP3, TNF, MYC, ESR1, and PTEN were likely direct targets of celastrol in OA. Finally, mTOR was determined as the most likely therapeutic target of celastrol in OA.

Conclusion

This study provides a basic understanding and novel insight into the potential mechanism of celastrol against OA.

Key Points

• Our study provides a strong indication that further study of celastrol therapy in OA is required.

• mTOR is the most likely therapeutic target of celastrol in OA.

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Data availability

The associated raw sequencing data in this study has been deposited in the Sequence Read Archive (SRA) under accession ID PRJNA602231. All other data generated or analyzed during this study are included within the article and its supplementary files.

Abbreviations

BP:

Biological process

CC:

Cellular component

DMOADs:

Disease-modifying osteoarthritis drugs

GO:

Gene ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MD:

Molecular dynamics

MF:

Molecular function

OMIM:

Online Mendelian Inheritance in Man

OA:

Osteoarthritis

PPI:

Protein-protein interaction

PDB:

Protein Data Bank

RMSD:

Root-mean-square deviation

SRA:

Sequence Read Archive

SEArch:

Similarity ensemble approach

TCMSP:

Traditional Chinese medicine systems pharmacology

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81771748) and Harbin Technology Bureau Research Fund (2017RAQXJ196).

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China

    Siming Dai, Hui Wang, Yue Zhang, Zhiyi Zhang & Zhiguo Lin

  2. Key Laboratory of Basic and Applied Research in North Medicine, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China

    Meng Wang

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  1. Siming Dai
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Correspondence to Zhiyi Zhang or Zhiguo Lin.

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Dai, S., Wang, H., Wang, M. et al. Comparative transcriptomics and network pharmacology analysis to identify the potential mechanism of celastrol against osteoarthritis. Clin Rheumatol 40, 4259–4268 (2021). https://doi.org/10.1007/s10067-021-05726-3

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