Drug Repurposing: Therapeutic Role of Aripiprazole in the Cartilage Defect

Abstract

Owing to the limited regenerative capacity of articular cartilage, damaged cartilage does not spontaneously heal over time. Various scientific efforts have been made to improve damaged articular cartilage. Nevertheless, no single approach has achieved a promising outcome for the damaged cartilage. Meanwhile, owing to the increasing cost of drug development, drug repositioning has been actively attempted. We aimed to identify the drug that can improve the cartilage defect, using chondrogenesis related microarray data recruited from the Gene Expression Omnibus (GEO) public database. Furthermore, we attempted to experiment using cellular and animal models to verify the cartilage regeneration potential for the identified drug. To screen for drugs that promote cartilage restoring, chondrogenesis related microarray data were collected from the GEO public database. The GSE69110, GSE107649, GSE111822, and GSE116173 datasets from the GEO were used to identify cartilage differentiation-related genes. Differentially expressed genes were identified using StringTie, and drug data were extracted from the Drug-Gene Interaction database. The effect of aripiprazole on cartilage was evaluated in aripiprazole-treated adipose-derived mesenchymal stem cells (ADMSCs) and chondrocyte using qRT-PCR and 3D pellet culture. The cartilage restoring efficacy was verified in vivo by mixing it with a scaffold and introducing it into the artificially damaged cartilage of Sprague-Dawley rats. Next, mRNA was sequenced for mechanistic analysis. As a result, aripiprazole significantly increased the mRNA expression of COL2A1 and SOX9, two cartilage differentiation-related genes, and chondrogenic condensation in vitro. Moreover, it effectively promoted cartilage regeneration in the cartilage defect rat model. Analysis of mRNA sequencing data from chondrocyte treated with aripiprazole, using KEGG and GOBP, indicated that aripiprazole significantly upregulates genes associated with ribosomes and cytoplasmic translation, thus promoting chondrogenesis. In conclusion, we discovered that aripiprazole can effectively improve damaged cartilage, providing a promising approach for cartilage regeneration.