Epoxymicheliolide inhibits osteoclastogenesis and resists OVX-induced osteoporosis by suppressing ERK1/2 and NFATc1 signaling

Long, Feng; Chen, Runfeng; Su, Yuangang; Liang, Jiamin; Xian, Yansi; Yang, Fan; Lian, Haoyu; Xu, Jiake; Zhao, Jinmin; Liu, Qian

doi:10.1016/j.intimp.2022.108632

Cited by 10 publications

(9 citation statements)

References 42 publications

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“…An OVX mouse model was constructed to validate if MRL could inhibit the function of osteoclasts and osteoporosis in vivo. The OVX mouse model has the same features of bone loss as postmenopausal women (22). CT results indicated that MRL could dramatically reduce bone loss compared to the OVX group.…”

Section: Discussionmentioning

confidence: 91%

“…Osteoporosis, an osteolytic bone disease, has the characteristics of bone homeostasis disturbance, mass bone decline, and bone microstructure degeneration (34,35) and is one of the most common diseases among middle-aged and older adults in the world (8,22). It is closely regulated by two main cell types: osteoclasts and osteoblasts, which are regulated by coupling activity.…”

Section: Discussionmentioning

confidence: 99%

“…NFATc1, the critical osteoclastogenesis-controlling master transcription factor, is subsequently initiated to express by RANKL (10). Eventually, transcription factor NFATc1 induces the expression of genes encoding osteoclast-relevant proteins, including TRAP, cathepsin K (CTSK), ATPase H + transporting v0 subunit d2 (Atp6v0d2) (6,22), matrix metalloproteinase (Mmp9) (6) and dendritic cellspeci c transmembrane protein (Dcstamp) (10), which promote osteoclast formation and then lead to bone resorption. Among the rest, the MAPK signaling pathway is pivotal in osteoclast differentiation (23,24), which comprises ERK, P38, and c-Jun N-terminal kinase (JNK).…”

Section: Introductionmentioning

confidence: 99%

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Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Chen

Gan

Wang

et al. 2023

Preprint

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Background Numerous studies have confirmed that activated osteoclasts cause excessive bone resorption, disrupting bone homeostasis and leading to osteoporosis. Moreover, ERK signaling is the classical pathway related to osteoclast differentiation. Besides, reactive oxygen species (ROS) is mainly from mitochondria, which is closely associated with the differentiation of osteoclasts. Myrislignan (MRL), a natural product derived from nutmeg, has various pharmacological activities. However, its effect on the treatment of osteoporosis is unclear. Therefore, this study mainly investigated whether MRL could inhibit osteoclastogenesis and bone mass loss in ovariectomy (OVX) mice via suppressing mitochondrial function and ERK signaling.Methods Tartrate-resistant and phosphatase (TRAP) assay and bone resorption assay were used to observe the effect of MRL on osteoclastogenesis. Furthermore, we added MitoSOX RED and tetramethyl rhodamine methyl ester (TMRM) staining to test the inhibitory effect of MRL on mitochondria. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay detected whether MRL suppressed the expression of specific genes in osteoclasts. The impact of MRL on mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) related proteins was evaluated by western blotting. Besides, a specific ERK agonist LM22B-10 (LM), was added to revalidate the inhibitory effect of MRL on ERK. Moreover, we established an OVX mouse model to assess the therapeutic effect of MRL on osteoporosis in vivo.Results MRL was proven to press osteoclast differentiation and bone resorption function, significantly reducing osteoclastic gene expression. Mechanistically, MRL inhibited the phosphorylation of ERK by suppressing the role of mitochondria, causing the downregulation of nuclear factor of activated T cells 1 (NFATc1) signaling. The experiment result of adding LM further clarified the targeted inhibition effect of MRL on ERK. The results of microscopic computed tomography (Micro-CT) and histology sections of the tibia in vivo indicated that OVX mice had lower bone mass and higher expression of ERK. However, after the MRL application, these results were significantly reversed, suggesting that MRL had a decent anti-osteoporosis effect.Conclusion We saw for the first time that MRL could inhibit ERK signaling by suppressing mitochondrial function, thus reducing OVX-induced osteoporosis. This novel finding could provide a broad prospect for the treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Chen

Gan

Wang

et al. 2023

Preprint

Self Cite

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“…The interaction between RANK from osteoclasts and RANKL precedes a downstream signal along the MAPK or NF-κB pathway to stimulate nuclear factor of activated T cells 1 (NFATc1) [95,96]. Then, NFATc1-mediated expression of protease-like cathepsin K (CTSK) or matrix metalloproteinase-9 (MMP-9) triggers the degradation of the collagen structure in bone, which recruits C-telopeptide of collagen Type 1 (CTX-1) in blood [34,97].…”

Section: Osteoporosismentioning

confidence: 99%

“…Bone marrow stem cells or bone marrow-derived macrophages differentiate into osteoclasts in the presence of macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) [ 94 ]. The interaction between RANK from osteoclasts and RANKL precedes a downstream signal along the MAPK or NF-κB pathway to stimulate nuclear factor of activated T cells 1 (NFATc1) [ 95 , 96 ]. Then, NFATc1-mediated expression of protease-like cathepsin K (CTSK) or matrix metalloproteinase-9 (MMP-9) triggers the degradation of the collagen structure in bone, which recruits C-telopeptide of collagen Type 1 (CTX-1) in blood [ 34 , 97 ].…”

Section: Anti-menopausal Effects Of Lignansmentioning

confidence: 99%

Antioxidant, Anti-Inflammatory, Anti-Menopausal, and Anti-Cancer Effects of Lignans and Their Metabolites

Jang

Kim

Cho

2022

IJMS

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Since chronic inflammation can be seen in severe, long-lasting diseases such as cancer, there is a high demand for effective methods to modulate inflammatory responses. Among many therapeutic candidates, lignans, absorbed from various plant sources, represent a type of phytoestrogen classified into secoisolariciresionol (Seco), pinoresinol (Pino), matairesinol (Mat), medioresinol (Med), sesamin (Ses), syringaresinol (Syr), and lariciresinol (Lari). Lignans consumed by humans can be further modified into END or ENL by the activities of gut microbiota. Lignans are known to exert antioxidant and anti-inflammatory activities, together with activity in estrogen receptor-dependent pathways. Lignans may have therapeutic potential for postmenopausal symptoms, including cardiovascular disease, osteoporosis, and psychological disorders. Moreover, the antitumor efficacy of lignans has been demonstrated in various cancer cell lines, including hormone-dependent breast cancer and prostate cancer, as well as colorectal cancer. Interestingly, the molecular mechanisms of lignans in these diseases involve the inhibition of inflammatory signals, including the nuclear factor (NF)-κB pathway. Therefore, we summarize the recent in vitro and in vivo studies evaluating the biological effects of various lignans, focusing on their values as effective anti-inflammatory agents.

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Corylifol A protects against ovariectomized-induced bone loss and attenuates RANKL‐induced osteoclastogenesis via ROS reduction, ERK inhibition, and NFATc1 activation

Song

Lin

et al. 2023

Free Radical Biology and Medicine

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Epoxymicheliolide inhibits osteoclastogenesis and resists OVX-induced osteoporosis by suppressing ERK1/2 and NFATc1 signaling

Cited by 10 publications

References 42 publications

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Antioxidant, Anti-Inflammatory, Anti-Menopausal, and Anti-Cancer Effects of Lignans and Their Metabolites

Corylifol A protects against ovariectomized-induced bone loss and attenuates RANKL‐induced osteoclastogenesis via ROS reduction, ERK inhibition, and NFATc1 activation

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