Liraglutide, a glucagon-like peptide-1 receptor agonist, suppresses osteoclastogenesis through the inhibition of NF-κB and MAPK pathways via GLP-1R

Abstract

Bone disorders such as osteoporosis, Paget’s disease of the bone, osteogenesis imperfecta, are caused by the uncoordinated action of osteoclasts and osteoblasts. Inhibiting osteoclastogenesis and suppressing the resorptive function of osteoclasts might become a gold standard strategy for treating this kind of disease. Glucagon-like peptide-1 (GLP-1) and its receptor agonist have been reported to have protective effects on bone. Little is known about the effect of GLP-1 on osteoclasts. Therefore, we investigated the effects of liraglutide, a GLP-1 receptor agonist, on murine bone marrow-derived macrophage (BMM) and RAW264.7 preosteoclast differentiation and explored the potential cellular basis of its action. In this study, we confirmed the presence of GLP-1 receptor (GLP-1R) on BMMs and RAW264.7 cells and demonstrated that GLP-1R might be important for osteoclastogenesis by increasing the expression of osteoclastogenic biomarkers after GLP-1R knockdown. In addition, we found that liraglutide treatment of both BMMs and RAW264.7 cells could inhibit osteoclast formation and bone resorption. Mechanistically, Western blotting and RT-PCR showed that liraglutide inhibited the NF-κB and MAPK signalling pathways, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). In addition, knocking down GLP-1R reversed the inhibitory effect of liraglutide on NF-κB/MAPK-NFATc1. Overall, these results indicated a potential therapeutic effect of liraglutide on bone disorders.