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

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.

Recent Advances in Osteoclast Biological Behavior

“…Loss of RANKL in mice results in severe osteopetrosis, while overexpression of soluble RANKL leads to severe osteoporosis ( Kong et al, 1999 ; Mizuno et al, 2002 ). When monocytes expressing RANK, a member of the TNF receptor family, are exposed to RANKL, they merge to create multinucleated osteoclasts ( Li Y.-X. et al, 2020 ).…”

Hesperetin affects osteoclast differentiation via MAPK signaling pathway

“…18 TAK1/TAB2, which is a downstream protein of TARF6 in the RANK signaling pathway, activates JNK with p38 protein. 27 Furthermore, downstream signaling of the ERK and JNK pathways include AP-1 transcription factors, Fos family dimers (c-Fos, FosB, Fra-1, and Fra-2) and Jun family (c-Jun, JunB, and JunD). 28 ERK could induce and activate c-Fos, while JNK could enhance the transcriptional activity of AP-1 through the phosphorylation of c-Jun.…”

Circulating Exosomes from Mice with LPS-Induced Bone Loss Inhibit Osteoblast Differentiation

“…Many factors are involved in the process of LPS-induced bone loss, including the local host response, production of prostaglandins and cytokines, and recruitment of inflammatory cells [ 10 , 11 ]. Recent studies have indicated that the bone loss caused by LPS is not only due to osteoclast activation, but also the inhibition of osteoblast function [ 12 – 14 ]. LPS promotes osteoblast apoptosis and inhibits osteoblast differentiation via activation of the JNK pathway in MC3T3-E1 cells [ 13 ].…”