Peiminine Suppresses RANKL-Induced Osteoclastogenesis by Inhibiting the NFATc1, ERK, and NF-κB Signaling Pathways

Abstract

Osteoclasts (OCs) play an important role in osteoporosis, a disease that is mainly characterized by bone loss. In our research, we aimed to identify novel approach for regulating osteoclastogenesis and thereby treating osteoporosis. Previous studies have set a precedent for screening traditional Chinese herbal extracts for effective inhibitors. Peiminine is an alkaloid extracted from the bulb of Fritillaria thunbergii Miq that reportedly has anticancer and anti-inflammatory effects. Thus, the potential inhibitory effect of peiminine on OC differentiation was investigated via a series of experiments. According to the results, peiminine downregulated the levels of specific genes and proteins in vitro and consequently suppressed OC differentiation and function. Based on these findings, we further investigated the underlying molecular mechanisms and identified the NF-κB and ERK1/2 signaling pathways as potential targets of peiminine. In vivo, peiminine alleviated bone loss in an ovariectomized mouse model.

Water Extract of Fritillariae thunbergii Bulbus Inhibits RANKL-Mediated Osteoclastogenesis and Ovariectomy-Induced Trabecular Bone Loss

“…The activation of NF-κB and MAPK pathways plays key roles in osteoclastogenesis and bone resorption in inflammatory bone loss [ 40 , 41 ]. Recently, it was reported that peiminine suppresses OVX-induced bone loss by inhibiting osteoclastogenesis through the suppression of RANKL-induced NFATc1, ERK, and NF-κB signaling pathways [ 42 ]. In this study, we found that WEFT suppressed osteoclastogenesis by inhibiting NFATc1, MAPK (ERK and JNK), and NF-κB signaling pathways.…”

Bardoxolone methyl ameliorates osteoarthritis by inhibiting osteoclastogenesis and protecting the extracellular matrix against degradation

“…NF-κB pathway is considered a crucial downstream factor in the RANKL-induced differentiation of OC and is critical for NFATc1 activation [ 46 , 51 ]. RANKL can induce the phosphorylation of IκB, and phosphorylated p65 enters the nucleus to activate NFATc1 expression [ 52 ]. In the meantime, NF-κB mediates chondrocyte catabolism in response to IL-1β stimulation, which contributes to the increased expression of MMP13 and ADAMTS-5, resulting in ECM damage [ 53 ].…”

Efficacy, chemical composition, and pharmacological effects of herbal drugs derived from Fritillaria cirrhosa D. Don and Fritillaria thunbergii Miq.

“…Moreover, studies have shown that NF-κB and ERK1/2 signaling pathways are possible targets of peimine. Peimine was described to attenuate bone loss from an ovariectomized mouse by inhibiting the NFATc1, ERK, and NF-κB signaling pathways, thus suppressing the receptor activator of nuclear factor kappa-Β ligand (RANKL), which is involved in osteoclastogenesis ( Zhu et al, 2021 ). In vitro experiments have shown that FRT-derived verticinone has a hypoglycemic effect mediated by increased insulin secretion, glucose uptake, and inhibition of carbohydrate hydrolase activity ( Boojar et al, 2020 ).…”