Identification of key regulators responsible for dysregulated networks in osteoarthritis by large-scale expression analysis

• DOI: 10.1186/s13018-021-02402-9
• Publication Date: 2021-04-14T11:03:37Z
• Authors: Song Shi; Fuyin Wan; Zhenyu Zhou; Ran Tao; Yue Lu; Ming Zhou; Fan Liu; Yake Liu
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; Male; Vascular Endothelial Growth Factor A; 0301 basic medicine; Transcriptional profiling; Proto-Oncogene Proteins c-jun; Drug repurposing; Gene Expression; Diseases of the musculoskeletal system; Cardiac Glycosides; 03 medical and health sciences; Osteoarthritis; Humans; Molecular Targeted Therapy; Protein Interaction Maps; Orthopedic surgery; 2. Zero hunger; 0303 health sciences; Forkhead Box Protein O3; Drug Repositioning; Computational Biology; 3. Good health; RC925-935; Female; RD701-811; Research Article; Genome-Wide Association Study; Transcription Factors

Abstract Background Osteoarthritis (OA) is a worldwide musculoskeletal disorder. However, disease-modifying therapies for OA are not available. Here, we aimed to characterize the molecular signatures of OA and to identify novel therapeutic targets and strategies to improve the treatment of OA.

Methods We collected genome-wide transcriptome data performed on 132 OA and 74 normal human cartilage or synovium tissues from 7 independent datasets. Differential gene expression analysis and functional enrichment were performed to identify genes and pathways that were dysregulated in OA. The computational drug repurposing method was used to uncover drugs that could be repurposed to treat OA.

Results We identified several pathways associated with the development of OA, such as extracellular matrix organization, inflammation, bone development, and ossification. By protein-protein interaction (PPI) network analysis, we prioritized several hub genes, such as JUN, CDKN1A, VEGFA, and FOXO3. Moreover, we repurposed several FDA-approved drugs, such as cardiac glycosides, that could be used in the treatment of OA.

Conclusions We proposed that the hub genes we identified would play a role in cartilage homeostasis and could be important diagnostic and therapeutic targets. Drugs such as cardiac glycosides provided new possibilities for the treatment of OA.