Arctiin abrogates osteoclastogenesis and bone resorption via suppressing RANKL-induced ROS and NFATc1 activation

Chen, Delong; Ye, Zhen; Wang, Chao; Wang, Qingqing; Wang, Haibin; Kuek, Vincent; Wang, Ziyi; Qiu, Heng; Yuan, Jinbo; Kenny, Jacob; Yang, Fan; He, Jianbo; Liu, Yun; Wang, Gang; Zhang, Meng; Zhang, Gangyu; Wang, Junjian; Chen, Peng; Xu, Jiake

doi:10.1016/j.phrs.2020.104944

Cited by 39 publications

(34 citation statements)

References 50 publications

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“…Clinically, antiresorptive agents, such as alendronate, zoledronate, and denosumab, are widely used for the treatment of osteoporosis ( Leder et al, 2020 ). Unfortunately, these drugs can cause a number of side effects, including stroke, gastrointestinal discomfort, hypokalaemia, and osteonecrosis of the jaw ( Chen et al, 2019 ; Delong Chen et al, 2020 ). Considering these shortcomings, it is imperative to find effective drugs to treat unbalanced bone remodelling caused by excessive osteoclast activity ( Huang et al, 2015 ; Wantao Li et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Osteoclasts are multinucleated cells, that differentiate from monocytes/macrophages in the presence of M-CSF and RANKL ( Xiao Lin et al, 2019 ). When RANKL activates the receptor activator of nuclear factor-κB (RANK), the inner membrane portion of RANK reacts with tumour necrosis factor receptor-associated factor 6 (TRAF6) and activates a series of downstream signalling pathways, including AKT, nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and calcium signalling pathways ( Delong Chen et al, 2020 ). Furthermore, the differentiation, survival, multinucleation, and activation of osteoclasts are regulated by these pathways ( Dai et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Lin

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Osteoporosis, characterized by the destruction of bone resorption and bone formation, is a serious disease that endangers human health. Osteoporosis prevention and treatment has become one of the important research contents in the field of medicine. Acacetin, a natural flavonoid compound, could promote osteoblast differentiation, and inhibit osteoclast formation in vitro. However, the mechanisms of acacetin on osteoclast differentiation and type H vessel formation, as well as the effect of preventing bone loss, remain unclear. Here, we firstly used primary bone marrow derived macrophages (BMMs), endothelial progenitor cells (EPCs), and ovariectomized (OVX) mice to explore the function of acacetin on bone remodeling and H type vessel formation. In this study, we found that acacetin inhibits osteoclast formation and bone resorption of BMMs induced by the macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) in a concentration of 20 μM without exerting cytotoxic effects. It was accompanied by downregulation of osteoclast differentiation marker genes (Ctsk, Acp5, and Mmp9) and cell fusion genes (CD9, CD47, Atp6v0d2, Dc-stamp, and Oc-stamp). Moreover, acacetin disrupted actin ring formation and extracellular acidification in osteoclasts. Mechanistic analysis revealed that acacetin not only inhibits the expression of the major transcription factor NFATc1 and NF-κB during RANKL-induced osteoclast formation, but also suppresses RANKL-induced the phosphorylation of Akt, GSK3β, IκBα, and p65. Additionally, acacetin enhanced the ability of M-CSF and RANKL-stimulated BMMs to promote angiogenesis and migration of EPCs. We further established that, in vivo, acacetin increased trabecular bone mass, decreased the number of osteoclasts, and showed more type H vessels in OVX mice. These data demonstrate that acacetin prevents OVX-induced bone loss in mice through inhibition of osteoclast function and promotion of type H vessel formation via Akt/GSK3β and NF-κB signalling pathway, suggesting that acacetin may be a novel therapeutic agent for the treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Lin

Zhang

et al. 2022

Front. Cell Dev. Biol.

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“…Through PubMed literature retrieval, we found that, among these common pathways, osteoclast differentiation, calcium signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway were most reported. Previous studies have shown that the suppression of RANKL-induced calcium signaling inhibits OP in oophorectomy (OVX) mouse models ( Chen et al, 2020 ). MAPK pathway is a major signaling pathway regulating OP.…”

Section: Resultsmentioning

confidence: 99%

Uncovering Hidden Mechanisms of Different Prescriptions Treatment for Osteoporosis via Novel Bioinformatics Model and Experiment Validation

Liu

Yin

et al. 2022

Front. Cell Dev. Biol.

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Osteoporosis (OP) is a systemic disease susceptible to fracture due to the decline of bone mineral density and bone mass, the destruction of bone tissue microstructure, and increased bone fragility. At present, the treatments of OP mainly include bisphosphonates, hormone therapy, and RANKL antibody therapy. However, these treatments have observable side effects and cannot fundamentally improve bone metabolism. Currently, the prescription of herbal medicine and their derived proprietary Chinese medicines are playing increasingly important roles in the treatment of OP due to their significant curative effects and few side effects. Among these prescriptions, Gushukang Granules (GSK), Xianling Gubao Capsules (XLGB), and Er-xian Decoction (EXD) are widely employed at the clinic on therapy of OP, which also is in line with the compatibility principle of “different treatments for the same disease” in herbal medicine. However, at present, the functional interpretation of “different treatments for the same disease” in herbal medicine still lacks systematic quantitative research, especially on the detection of key component groups and mechanisms. To solve this problem, we designed a new bioinformatics model based on random walk, optimized programming, and information gain to analyze the components and targets to figure out the Functional Response Motifs (FRMs) of different prescriptions for the therapy of OP. The distribution of high relevance score, the number of reported evidence, and coverage of enriched pathways were performed to verify the precision and reliability of FRMs. At the same time, the information gain and target influence of each component was calculated, and the key component groups in all FRMs of each prescription were screened to speculate the potential action mode of different prescriptions on the same disease. Results show that the relevance score and the number of reported evidence of high reliable genes in FRMs were higher than those of the pathogenic genes of OP. Furthermore, the gene enrichment pathways in FRMs could cover 79.6, 81, and 79.5% of the gene enrichment pathways in the component-target (C-T) network. Functional pathway enrichment analysis showed that GSK, XLGB, and EXD all treat OP through osteoclast differentiation (hsa04380), calcium signaling pathway (hsa04020), MAPK signaling pathway (hsa04010), and PI3K-Akt signaling pathway (hsa04151). Combined with experiments, the key component groups and the mechanism of “different treatments for the same disease” in the three prescriptions and proprietary Chinese medicines were verified. This study provides methodological references for the optimization and mechanism speculation of Chinese medicine prescriptions and proprietary Chinese medicines.

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“…As a consequence of bone-related aging diseases, SOP is one of the most common types of osteoporosis, which results in an increased risk to fragility fracture among the elderly. As the age grows, the level of ROS is increased and then leads to the enhancement of osteoclastic activity and bone destruction [ 25 , 26 ]. The current study demonstrated that OG suppressed bone loss in SAMP6 mice and osteoclastogenesis from macrophagic RAW264.7 cells under the induction of RANKL and H 2 O 2 through attenuating oxidative stress and autophagy via activating the Nrf2/Keap1 and mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Orcinol Glucoside Improves Senile Osteoporosis through Attenuating Oxidative Stress and Autophagy of Osteoclast via Activating Nrf2/Keap1 and mTOR Signaling Pathway

Gong

Liu

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Oxidative stress and autophagy play essential roles in the development of senile osteoporosis which is characterized by disrupted osteoclastic bone resorption and osteoblastic bone formation. Orcinol glucoside (OG), a phenolic glycoside isolated from Curculigo orchioides Gaertn, possesses antiosteoporotic properties. This study examined the protective effects of OG on bone loss in SAMP6 mice and explored the underlying mechanisms. The osteoporotic SAMP6 mice were treated with OG oral administration. RAW264.7 cells were induced to differentiate into osteoclast by RANKL and H2O2 in vitro and received OG treatment. The results demonstrated that OG attenuated bone loss in SAMP6 mice and inhibited the formation and bone resorption activities of osteoclast and reduced levels of oxidative stress in bone tissue of SAMP6 mice and osteoclast. Furthermore, OG activated Nrf2/Keap1 signaling pathway and enhanced the phosphorylation of mTOR and p70S6K which are consequently suppressing autophagy. Of note, the effect of OG on Nrf2/Keap1 signaling was neutralized by the mTOR inhibitor rapamycin. Meanwhile, the inhibitory effect of OG on autophagy was reversed by the Nrf2 inhibitor ML385.Conclusively, OG attenuated bone loss by inhibiting formation, differentiation, and bone resorption activities of osteoclast. Regulation of Nrf2/Keap1 and mTOR signals is a possible mechanism by which OG suppressed oxidative and autophagy of osteoclasts. Thus, OG prevented senile osteoporosis through attenuating oxidative stress and autophagy of osteoclast via activating Nrf2/Keap1 and mTOR signaling pathway.

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Arctiin abrogates osteoclastogenesis and bone resorption via suppressing RANKL-induced ROS and NFATc1 activation

Cited by 39 publications

References 50 publications

Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Uncovering Hidden Mechanisms of Different Prescriptions Treatment for Osteoporosis via Novel Bioinformatics Model and Experiment Validation

Orcinol Glucoside Improves Senile Osteoporosis through Attenuating Oxidative Stress and Autophagy of Osteoclast via Activating Nrf2/Keap1 and mTOR Signaling Pathway

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