Pantoprazole (PPZ) Inhibits RANKL-Induced Osteoclast Formation and Function In Vitro and Prevents Lipopolysaccharide- (LPS-) Induced Inflammatory Calvarial Bone Loss In Vivo.

Yu-Xi Li,Jia-Jun Huang,Ting Liu,Lin Huang,Jun-Shen Huang,Zhao-Peng Cai,Guo-Xue Tang,Xiang-Ge Liu,Fu-Chao Chen,Keng Chen,Peng Wang,Yu-Wei Liang,Mahmood S Choudhery

doi:10.1155/2020/8829212

Abstract

Bone remodeling is a process delicately balanced between osteoclastic bone resorption and osteoblastic bone formation. Osteoclasts (OCs) are multinucleated giant cells formed through the fusion of monocytic precursors of the hematopoietic stem cells lineage. OCs are the exclusive cells responsible for the resorption and degradation of the mineralized bone matrix. Pantoprazole (PPZ), a proton pump inhibitor (PPI), is commonly prescribed to reduce excess gastric acid production for conditions such as gastroesophageal reflux disease and peptic ulcer disease. Studies have found contradictory effects of PPI therapy on bone metabolism due to the lack of understanding of the exact underlying mechanism. In this study, we found that PPZ inhibits receptor activator of nuclear factor-κB (NF-κB) ligand- (RANKL-) induced osteoclastogenesis from bone marrow monocytic/macrophage (BMMs) precursors and the bone-resorbing activity of mature OCs. Correspondingly, the expression of OC marker genes was also attenuated. At the molecular level, PPZ treatment was associated with reduced activation of the ERK MAPK signaling pathways crucial to OC differentiation. Additionally, the in vivo administration of PPZ protected mice against lipopolysaccharide- (LPS-) induced inflammatory calvarial bone erosion, as a result of the reduced number and activity of OCs on the calvarial bone surface. Although PPI use is associated with increased risk of osteoporosis and bone fractures, our study provides evidence for the direct inhibitory effect of PPZ on OC formation and bone resorption in vitro and in vivo, suggesting a potential therapeutic use of PPZ in the treatment of osteolytic disease with localized bone destruction.

Highlights

Proton pump inhibitors (PPIs) such as pantoprazole (PPZ) are well-established standard treatment strategy for the treatment of upper gastrointestinal disorders such as gastroesophageal reflux disease and peptic ulcers
bone marrow monocytes/macrophages (BMMs) were exposed to serial dilutions of PPZ starting from 100 μM down to 0.375 μM for 48 and 72 hrs after which cell viability/proliferation was evaluated by the MTT assay
The results showed that BMM viability was not affected by PPZ at concentrations of up to 12.5 μM in a 72-hour experiment (Figures 1(b) and 1(c))

Summary

Introduction

Proton pump inhibitors (PPIs) such as pantoprazole (PPZ) are well-established standard treatment strategy for the treatment of upper gastrointestinal disorders such as gastroesophageal reflux disease and peptic ulcers. PPZ was developed in Germany in October 1994 and was marketed in South Africa in the same year. Pantoprazole is a third-generation proton pump inhibitor, and its efficacy and safety have been fully confirmed. PPZ is usually administered clinically by injection or oral. The usual dose of pantoprazole sodium for injection is 40 mg twice daily. The oral dosage for the treatment of peptic ulcers and related diseases is usually 40 mg once a day. PPIs irreversibly bind to the H+/K+-ATPase or the proton pumps in the apical surface of parietal cells in the stomach to inhibit acid secretion

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