BOS as a Novel Strategy for Bone Regeneration

Background: Bone regeneration after critical-size defects remains a major clinical challenge, and current grafting approaches are limited by their morbidity, immunogenicity, and availability. Pharmacological strategies that harness the potential of endogenous stem cells offer a promising alternative. Endothelin-1 (ET-1), a potent vasoactive peptide, exerts context-dependent effects on bone remodeling through ETA and ETB receptors. Excessive ET-1 signaling is associated with osteoclast activation, inflammation, and bone loss, suggesting that endothelin receptor antagonists like Bosentan (BOS) may provide skeletal benefits. Objective: To investigate whether BOS, a clinically approved dual ETA/ETB antagonist currently used for pulmonary arterial hypertension, can be repositioned to promote osteogenesis in human periodontal ligament stem cells (hPDLSCs). Methods: hPDLSCs were isolated and characterized according to mesenchymal stem cell criteria. Cells were treated with increasing concentrations of BOS (10–40 µM), and assays were performed to evaluate cytotoxicity (MTT), migration (scratch assay), mineralization (Alizarin Red S staining), alkaline phosphatase (ALP) activity, and gene expression of osteogenic (RUNX2, OPG, CTNNB1) and inflammatory (TNF-α) markers. Results: BOS was non-cytotoxic at all tested concentrations. At 30–40 µM, BOS significantly enhanced cell migration, mineralized nodule formation, and ALP activity compared to osteogenic controls (p Conclusion: BOS augments hPDLSC-mediated osteogenesis by activating osteoblastogenic pathways, enhancing mineralization, and reducing inflammatory cytokine expression. These findings suggest that BOS is a promising candidate for drug repurposing in bone regeneration.