Inhibiting Monoacylglycerol Lipase Suppresses RANKL-Induced Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss.

Hui Liu,Dahu Qi,Meipeng Zhu,Chuankun Zhou,Xuying Sun,Yutong Gao,Tenghui Tao,Jun Xiao

doi:10.3389/fcell.2021.640867

Abstract

Osteoporosis is a common chronic metabolic bone disease characterized by reduced trabecular bone and increased bone fragility. Monoacylglycerol lipase (MAGL) is a lipolytic enzyme to catalyze the hydrolysis of monoglycerides and specifically degrades the 2-arachidonoyl glycerol (2-AG). Previous studies have identified that 2-AG is the mainly source for arachidonic acid and the most abundant endogenous agonist of cannabinoid receptors. Considering the close relationship between inflammatory mediators/cannabinoid receptors and bone metabolism, we speculated that MAGL may play a role in the osteoclast differentiation. In the present study, we found that MAGL protein expression increased during osteoclast differentiation. MAGL knockdown by adenovirus-mediated shRNA in bone marrow-derived macrophages demonstrated the suppressive effects of MAGL on osteoclast formation and bone resorption. In addition, pharmacological inhibition of MAGL by JZL184 suppressed osteoclast differentiation, bone resorption, and osteoclast-specific gene expression. Activation of the Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways was inhibited by JZL184 and deletion of MAGL. Our in vivo study indicated that JZL184 ameliorated bone loss in an ovariectomized mouse model. Furthermore, overexpressing H1 calponin partially alleviated the inhibition caused by JZL184 or MAGL deletion on osteoclastogenesis. Therefore, we conclude that targeting MAGL may be a novel therapeutic strategy for osteoporosis.

Highlights

Osteoporosis is a common chronic metabolic bone disease characterized by changes in bone mineral density and architecture (Henriksen et al, 2011; Rachner et al, 2011; Compston et al, 2019)
We evaluated the expression of Monoacylglycerol lipase (MAGL) during osteoclast differentiation to determine if MAGL is essential for osteoclastogenesis
bone marrow macrophages (BMMs) were cultured with macrophage colony-stimulating factor (M-CSF) and RANKL for up to 5 days, and the mRNA and protein levels of the majority of the osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase-9 (MMP-9), c-FOS, and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) increased gradually during osteoclast differentiation (Figures 1A,B)

Summary

Introduction

Osteoporosis is a common chronic metabolic bone disease characterized by changes in bone mineral density and architecture (Henriksen et al, 2011; Rachner et al, 2011; Compston et al, 2019). The balance between bone formation by osteoblasts and bone resorption by osteoclasts continuously maintains bone homeostasis (Boyce, 2013). This process involves intricate factors, such as hormones, nutrition, drugs, and external biomechanical stimuli (Zhang et al, 2015). The current therapies for osteoporosis primarily target antiresorptive and anabolic agents, including bisphosphonates, calcitonin, estrogens, denosumab, and teriparatide (Rachner et al, 2011). These drugs alleviate symptoms, side effects should not be neglected.

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