Lansoprazole-Induced Osteoporosis via IP3R and SOCE Mediated Calcium Signaling Pathway
Abstract
Abstract Background: Many clinical studies have shown a correlation between proton pump inhibitors (PPIs) and osteoporosis or fractures. The purposes of this study were to establish a murine model of chronic oral administration of PPIs to verify whether PPIs caused bone metabolic impairment, and to investigate the relevant molecular mechanism underlying the effects of PPIs on MC3T3-E1 mouse osteoblasts.Methods: Lansoprazole-induced bone loss model was employed to investigate the damage effects of PPIs. In vivo, immunohistochemistry and HE staining, micro-CT analysis, blood biochemical tests were used to evaluate the effect of lansoprazole on bone injury in mice. In vitro, the effects and related signaling pathway of lansoprazole on MC3T3-E1 cells were investigated by CCK8, EDU kit, flow cytometry, laser confocal, patch clamp, PCR and Western blotting, etc.Results: After 6 months of lansoprazole gavage in ICR mice, micro-CT results showed that compared with the vehicle group, the bone mineral density (BMD) of high-dose group was significantly decreased (P<0.05), and the bone microarchitecture gradually degraded. Biochemical assay of bone serum found that blood calcium and phosphorus were both decreased (P<0.01). We found that long-term administration of lansoprazole impairs skeletal function in mice. In vitro, we found that lansoprazole (LPZ) could cause calcium overload in MC3T3-E1 cells leading to apoptosis, and 2-APB, an inhibitor of IP3R calcium release channel and SOC…
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