Drug Repositioning Based on Single-Cell Transcriptomics Data Identifies Quinidine as a Potential Drug for Treating Osteoporosis

Abstract

Osteoporosis (OP) is characterized by low bone mass and impaired bone microarchitecture, and the long-term use of current therapies is limited by adverse effects and poor adherence. This study sought to identify drugs that could be repurposed for glucocorticoid-induced osteoporosis. Methods: Single-cell RNA-sequencing data from two subjects with osteoporotic fractures and three control subjects were analyzed to identify transcriptional changes in osteoblasts. Candidate drugs were screened using ASGARD and L1000 drug-response signatures. Two-sample Mendelian randomization was used to examine associations between genetically predicted expression of drug-target genes and osteoporosis risk. Quinidine was tested in dexamethasone-treated Tu and Tg(Ola.Sp7:nlsGFP) zebrafish larvae using Alizarin Red staining, fluorescence imaging, and qRT-PCR. Adult zebrafish were assessed by micro-CT. Results: Four candidate drugs were identified, of which quinidine was selected for experimental evaluation. Genetically predicted SCN5A expression was positively associated with osteoporosis risk. Quinidine partially restored cranial mineralization in dexamethasone-treated larvae, with the greatest effect at 10 μmol/L; the 100 μmol/L treatment was less effective. Quinidine also altered the expression of several bone-remodeling-related genes. In adult zebrafish, quinidine treatment was associated with higher bone mineral density and bone volume fraction than dexamethasone treatment alone. Conclusions: Quinidine alleviated several dexamethasone-induced skeletal phenotypes in zebrafish and represents a candidate for further drug-repurposing studies in osteoporosis. Direct validation of its molecular mechanism and safety profile is still required.