Mechanisms by which mangiferin alleviates pain in osteoarthritis: integration of microarray data analysis, network pharmacology, and experimental validation in a rat model

Abstract

BACKGROUND: Mangiferin, a major bioactive compound derived from mango trees, is widely present in various traditional Chinese medicinal herbs and exhibits multiple biological functions including antibacterial, cholesterol-lowering, and anti-allergic effects. Existing studies have suggested that mangiferin may prevent and treat osteoarthritis pain. However, its specific mechanism of action remains unclear to date. OBJECTIVE: To systematically investigate the key targets and potential mechanisms of mangiferin in the treatment of osteoarthritis by integrating gene expression omnibus (GEO) microarray data analysis, network pharmacology, and molecular docking techniques, and to validate the findings in a rat model. METHODS: First, GEO microarray data were mined to identify potential therapeutic targets for osteoarthritis. Next, professional databases were integrated to predict the targets of mangiferin, and target information related to osteoarthritis was collected. A Venn diagram was generated using the Weishengxin platform, a protein-protein interaction network was constructed based on the STRING database, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Cytoscape 3.8.0 software was used to construct a drug-target-pathway-disease network, and molecular docking analysis and visualization were performed using the CBDOCK2 online docking platform. A rat model of osteoarthritis was established by anterior cruciate ligament transection of the left knee joint, and different concentrations of mangiferin were administered to observe and record the therapeutic effects. RESULTS AND CONCLUSION: A total of 144 potential targets of mangiferin were identified from multiple databases. Protein-protein interaction network analysis revealed important targets including interleukin-6, tumor necrosis factor, and nuclear factor kappa B1. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that 235 signaling pathways might be involved, including lipid and atherosclerosis-related pathways, advanced glycation end products-receptor, hypoxia-inducible factor 1, and estrogen, which are closely related to inflammation. In animal experiments, after 4 weeks of intervention with 40 μmol/L mangiferin, there was no significant difference in hindlimb weight-bearing compared with the sham-operated group. These findings suggest that mangiferin may exert therapeutic effects on osteoarthritis through a multi-target, multi-pathway mode of action, providing a new strategy and theoretical support for the treatment of osteoarthritis.

1. Introduction

Osteoarthritis is a clinical syndrome characterized by joint pain, often accompanied by varying degrees of functional limitation and decreased quality of life. As the most common type of arthritis, it is not only a major cause of pain worldwide but also a significant factor in disability, most commonly affecting the knee, hip, and small joints of the hands. Although pain, reduced limb function, and decreased daily living ability may be important consequences of osteoarthritis, pain itself is a complex biopsychosocial issue [1]. Early arthritis can be improved through lifestyle changes, physical therapy, and medication, but advanced and end-stage arthritis generally requires surgical intervention, such as joint replacement [2]. Although drug therapy can improve the condition to some extent, there are obvious drawbacks, such as nonsteroidal anti-inflammatory drugs increasing the risk of cardiovascular events and gastrointestinal adverse reactions, potentially leading to stomach discomfort or acid reflux [3]. Given the limitations of existing treatments for osteoarthritis, traditional Chinese medicine has unique advantages in relieving pain, delaying disease progression, and improving quality of life. Therefore, exploring the effects of traditional Chinese medicine therapies has important academic and practical significance [4].

In traditional Chinese medicine theory, osteoarthritis is classified under the categories of 'Bi syndrome' and 'Gu Bi syndrome', with the etiology and pathogenesis attributed to liver and kidney deficiency, qi and blood deficiency, and invasion of external wind, cold, and dampness [5]. Mangiferin, a major bioactive component derived from mango trees, is also widely distributed in various Chinese herbal medicines. Its secondary metabolites exhibit multiple biological functions including antibacterial, cholesterol-lowering, anti-allergic, cardiotonic, anti-diabetic, anti-tumor, neuroprotective, antioxidant, and immunomodulatory activities [6]. Additionally, studies have suggested that mangiferin may have preventive and therapeutic effects on osteoarthritis pain [7]. This study integrates microarray data from the Gene Expression Omnibus (GEO) database, combined with network pharmacology and molecular docking techniques, to deeply explore the potential mechanisms and key targets of mangiferin in alleviating osteoarthritis pain, aiming to provide innovative insights for new drug development and clinical treatment strategies. Furthermore, animal experiments were conducted to validate the clinical efficacy of mangiferin in reducing osteoarthritis pain.