Druggable gene and single cell analyses reveal potential therapeutic targets for osteoporosis

Abstract

BACKGROUND: Genetic factors play an important role in the pathophysiology of osteoporosis, and Mendelian randomization can be used to infer causal associations between specific genes and diseases using eQTLs. OBJECTIVE: To identify potential therapeutic targets for osteoporosis based on druggable genes-related Mendelian randomization and colocalization analysis, to explore the potential biological mechanisms in the treatment of osteoporosis using bioinformatics analysis, and to predict the binding activity of drug targets using drug enrichment analysis and molecular docking. METHODS: (1) Data sources: Druggable genes were sourced from the DGIdb database (a public database constructed by the University of Washington School of Medicine, widely used for drug target discovery) and information provided in the literature. Expression quantitative trait locus (eQTL) data for druggable genes were obtained from eQTLGen (a large-scale blood eQTL database jointly constructed by multiple international research institutions, including the University of Groningen). Osteoporosis genome-wide association study (GWAS) data were obtained from FinnGen R12 (a large genomic database led by the University of Helsinki), including 10,461 osteoporosis cases and 473,264 controls. GEO datasets GSE230665 (microarray) and GSE169396 (single-cell) were also used. (2) Methods: Genes closely related to osteoporosis were screened; expression of genes in osteoporosis was evaluated via microarray data; single-cell analysis further observed the regulatory role of genes in cell communication; enrichment analysis was used to elucidate biological functions, and protein-protein interaction networks were constructed to analyze potential associations; drug enrichment and molecular docking predicted and simulated the binding of small molecule drugs to targets. RESULTS AND CONCLUSION: The study identified 37 druggable genes associated with osteoporosis, among which troponin C2 and CXC chemokine receptor 6 (CXCR6) had protective effects and shared causal genetic variants with the disease. Microarray data analysis showed that CXCR6 expression was significantly lower in osteoporosis than in normal controls, suggesting a weakened protective effect. Single-cell analysis further revealed that CXCR6 was mainly expressed on T cells, and CXCR6+ T cells exhibited stronger cell communication capabilities. Drug enrichment analysis found that NSC95397 could target CXCR6, and molecular docking showed good binding activity. These findings not only provide clues for the development of new drugs for osteoporosis but also facilitate the translation of research results.

1. Introduction

Osteoporosis is an orthopedic disease characterized by decreased bone mass, deterioration of bone microstructure, and increased bone fragility [1], with its prevalence gradually rising [2-3]. Osteoporosis directly exacerbates the risk of fractures, with approximately 50% of women and 20% of men experiencing osteoporotic fractures after age 50 [4]. The prognosis of osteoporotic fractures in the elderly is generally poor, often leading to complications such as pneumonia and deep vein thrombosis, and in severe cases, death [5-6], imposing a heavy burden on individuals and society.

In current clinical practice, common treatments for osteoporosis include bisphosphonates and estrogen preparations. Notably, many drug-related adverse reactions have been reported; osteonecrosis of the jaw has been closely associated with bisphosphonate use [7-8]. Additionally, bisphosphonate use may increase the risk of esophageal cancer [9]. In patients using estrogen preparations, the incidence of breast cancer, endometrial cancer, and ovarian cancer has shown a significant upward trend [10-11]. Furthermore, estrogen receptor modulators such as bazedoxifene have been reported to cause deep vein thrombosis, and in severe cases, pulmonary embolism [12]. Therefore, a deeper understanding of the molecular mechanisms of osteoporosis and the exploration of safer and more effective therapeutic targets are crucial for the prevention and treatment of osteoporosis.

With the continuous development of genome-wide association studies (GWAS), the research value of druggable genes has become increasingly prominent. By analyzing the expression patterns of druggable genes, researchers can efficiently screen key genes with druggable potential [13]. As instrumental variables, expression quantitative trait loci (eQTLs) occupy an important position in genetic research [14]. Mendelian randomization can use eQTLs to infer causal associations between specific genes and diseases [15]. Genetic factors also play an important role in the pathophysiology of osteoporosis. Based on this, this study used Mendelian randomization and colocalization analysis to explore the potential roles of druggable genes in osteoporosis, integrated multiple methods to screen key genes with clinical translational value [16], and thus provide clues for precision treatment of osteoporosis in China.