Neogambogic Acid Suppresses Receptor Activator of Nuclear Factor κB Ligand (RANKL)-Induced Osteoclastogenesis by Inhibiting the JNK and NF-κB Pathways in Mouse Bone Marrow-Derived Monocyte/Macrophages

Abstract

BackgroundNeogambogic acid (NGA) is used in traditional Chinese medicine. The aim of this study was to investigate the effects of NGA on gene signaling pathways involved in osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages (BMMs) and on bone resorption in vitro.Material/MethodsPrimary mouse BMMs were cultured with increasing concentrations of NGA. Real-time polymerase chain reaction was used to study the expression of mRNAs corresponding to gene products specific to receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, including tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), cathepsin K (CTSK), and nuclear factor of activated T cells c1 (NFATc1). A cell counting kit-8 assay was used to evaluate cell proliferation. Western blotting and confocal immunofluorescence microscopy were used to investigate the signaling pathways. A bone resorption model was used to quantify bone resorption.ResultsAn NGA dose of ≤0.4 μg/ml had no significant effect on the proliferation of mouse BMMs in vitro (P>0.05); concentrations of between 0.1–0.4 μg/ml significantly inhibited RANKL-induced osteoclastogenesis (P<0.01) in a dose-dependent manner. Compared with the control group, NGA significantly reduced RANKL-induced bone resorption in vitro (P <0.01), and downregulated the expression of osteoclast-related mRNAs of TRAP, CTR, CTSK, and NFATc1. NGA suppressed the activation of JNK but not the p38 signaling pathway and significantly reduced NF-κB p65 phosphorylation and the nuclear transport of NF-κB molecules, which inhibited NFATc1 expression.ConclusionsNGA suppressed RANKL-induced osteoclastogenesis by inhibiting the JNK and NF-κB pathways in mouse BMMs in vitro and reduced osteoclastic bone resorption.

Neogambogic acid relieves myocardial injury induced by sepsis via p38 MAPK/NF-κB pathway

“…LPS stimulated activation of p38 MAPK/NF-κB signaling, and inactivation of p38 MAPK/NF-κB signaling alleviated LPS-induced cardiac insufficiency [ 21 ]. Silica-induced up-regulation of p-p38 in macrophages was decreased by neogambogic acid [ 11 ], and neogambogic acid reduced p-JNK and p-NF-κB in receptor activator of nuclear factor κB ligand-induced mice [ 22 ]. This study revealed that neogambogic acid down-regulated protein expression of p-p38, p-JNK and p-NF-κB in heart tissues of septic mice, suggesting that neogambogic acid might alleviate sepsis induced cardiomyopathy through inactivation of p38 MAPK/NF-κB signaling.…”

How zoledronic acid improves osteoporosis by acting on osteoclasts

“…ZA treatment Frontiers in Pharmacology frontiersin.org can down-regulate JNK phosphorylation in a dose-dependent manner. However, ZA cannot significantly affect the phosphorylation levels of p38 and ERK, suggesting that ZA can specifically inhibit RANKL-induced JNK phosphorylation during osteoclast differentiation (Jin et al, 2018;Huang et al, 2019;Sun et al, 2020;Cheng et al, 2021;Huang et al, 2022). ZA can inhibit RANKL-induced downstream expression of c-Jun, c-Fos and nuclear factor of activation of T cells-1 (NFATc1).…”

“…Both the mitogen-activated protein kinases (MAPK) and NF-κB signaling pathways are closely related to osteoclast differentiation. The MAPK pathway, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, is critical for regulation of osteoclast differentiation ( Jin et al, 2018 ; Huang et al, 2019 ; Peng et al, 2021 ). ZA treatment can down-regulate JNK phosphorylation in a dose-dependent manner.…”

Transcriptional Analysis of the Effects of Gambogic Acid and Neogambogic Acid on Methicillin-Resistant Staphylococcus aureus

“…GA and NGA are two active compounds found in Garcinia species, which exhibit immune-enhancing, anti-inflammatory, antitumor, and proapoptotic activities (Wang et al, 2011; Chen et al, 2015; Zhang et al, 2016; Jin et al, 2018). Especially in the aspects of anti-inflammatory and anti-tumor, it has been found that gamoic acid can inhibit many cell signaling pathways, such as nuclear factor-kappa B (nf-κb), tumor necrosis factor-α (TNF-α), and iNOS (Pandey et al, 2016; Sun et al, 2018).…”