Tereticornate A suppresses RANKL-induced osteoclastogenesis via the downregulation of c-Src and TRAF6 and the inhibition of RANK signaling pathways

Liu, Titi; Jiang, Li; Xiang, Zemin; Li, Jin; Zhang, Yaqi; Xiang, Ting; Wang, Wei; Li, Xiaofeng; Jia, Yuankan; Huang, Xueqin; Lu, Xihong; Xu, Huanhuan; Sheng, Jun

doi:10.1016/j.biopha.2022.113140

Cited by 10 publications

(9 citation statements)

References 35 publications

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“…As is reported that mature multinuclear osteoclasts appear to increase mitochondria activity and ROS levels (52). And mature osteoclasts have a high energy requirement, while mitochondria are essential organelles to produce ATP through oxidative phosphorylation (13,35,53). Therefore, activating mitochondria to provide energy for osteoclast maturation is crucial.…”

Section: Discussionmentioning

confidence: 98%

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: 98%

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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“…In terms of osteoclastogenesis and bone resorption, the RANK/RANKL pathway is primarily responsible for the mechanism of action 44 . As a result, antiresorptive efficacy is acquired by the downregulation of RANK 6 . During bone resorption, mature osteoclasts require Mmp9, a degradative enzyme of the extracellular matrix 45 ; thus, Mmp9 has been recognized to be one of the osteoclast-specific markers 46 .…”

Section: Discussionmentioning

confidence: 99%

“…The receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) is a membrane-associated cytokine produced by osteoblasts 5 . When RANKL binds to the receptor RANK, made from osteoclast precursor, the remodelling process is activated, leading to osteoclastogenesis and the breakdown of the extracellular matrix 6 . Osteoprotegerin (OPG) is a soluble decoy receptor for RANKL made by osteoblast.…”

Section: Introductionmentioning

confidence: 99%

Allolobophora caliginosa coelomic fluid and extract alleviate glucocorticoid-induced osteoporosis in mice by suppressing oxidative stress and regulating osteoblastic/osteoclastic-related markers

Abdelfattah

Mohamed

Ibrahim

et al. 2023

Sci Rep

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Allolobophora calignosa (Ac) is a folk medicine for millennia, as it possesses many biological activities. This study aimed to investigate the chemo-preventive activity of A.calignosa coelomic fluid (AcCF) and A.calignosa extract (AcE) on glucocorticoid-induced osteoporosis (GIOP) in mice. Characterization and in vitro biological activity of AcE and AcCF has been assessed. Male CD-1 mice were subcutaneously received dexamethasone (DEX) (1 mg/kg, 5 times/week) and concurrently intraperitoneally treated with either AcCF (20 mg/kg) or AcE (45 mg/kg) every other day for 28 days. Serum and bone homogenates were subjected for qPCR and biochemical analysis. AcE and AcCF treatment significantly increased bone mineral density (BMD), bone mineral content (BMC), calcium (Ca), phosphorus (P), and calcitonin levels, whereas activity of serum alkaline phosphatase (ALP), bone alkaline phosphatase (BALP), serum acidic phosphatase (ACP), bone acidic phosphatase (BACP) and parathyroid hormone (PTH) levels were significantly reduced compare with untreated GIOP mice. Treatment with AcE and AcCF modulates oxidative stress and downregulated Rank and Mmp9 expression, as well as increased glycosaminoglycan content in the organic bone matrix, resulting in osteoclastogenesis inhibition. Overall, AcCF and AcE show a chemo-preventive activity against GIOP by inhibiting oxidative stress and regulating expression and/or activity of osteoblast/osteoclast-related markers.

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“…RT-qPCR results showed significant differences in the MAPK signaling pathway (p38, TRAF6) and NF-kappaB signaling pathway (c-FLIP, MIP1β). Previous studies have shown that OPG/RANK/RANKL ( 9 ), IL-1β ( 47 ),TRAF6 ( 48 ), NFATc1, OSCAR and NF-κB ( 49 ), and other genes related to apoptosis, inflammation, and osteogenic differentiation ( 6 ). These genes regulate bone metabolism via the MAPK signaling pathway and TNF signaling pathway, which affects OP.…”

Section: Discussionmentioning

confidence: 99%

Prognostic analysis and validation of diagnostic marker genes in patients with osteoporosis

Wang¹,

Pei²,

Hao³

et al. 2022

Front. Immunol.

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BackgroundsAs a systemic skeletal dysfunction, osteoporosis (OP) is characterized by low bone mass and bone microarchitectural damage. The global incidences of OP are high.MethodsData were retrieved from databases like Gene Expression Omnibus (GEO), GeneCards, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Gene Expression Profiling Interactive Analysis (GEPIA2), and other databases. R software (version 4.1.1) was used to identify differentially expressed genes (DEGs) and perform functional analysis. The Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and random forest algorithm were combined and used for screening diagnostic markers for OP. The diagnostic value was assessed by the receiver operating characteristic (ROC) curve. Molecular signature subtypes were identified using a consensus clustering approach, and prognostic analysis was performed. The level of immune cell infiltration was assessed by the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm. The hub gene was identified using the CytoHubba algorithm. Real-time fluorescence quantitative PCR (RT-qPCR) was performed on the plasma of osteoporosis patients and control samples. The interaction network was constructed between the hub genes and miRNAs, transcription factors, RNA binding proteins, and drugs.ResultsA total of 40 DEGs, eight OP-related differential genes, six OP diagnostic marker genes, four OP key diagnostic marker genes, and ten hub genes (TNF, RARRES2, FLNA, STXBP2, EGR2, MAP4K2, NFKBIA, JUNB, SPI1, CTSD) were identified. RT-qPCR results revealed a total of eight genes had significant differential expression between osteoporosis patients and control samples. Enrichment analysis showed these genes were mainly related to MAPK signaling pathways, TNF signaling pathway, apoptosis, and Salmonella infection. RT-qPCR also revealed that the MAPK signaling pathway (p38, TRAF6) and NF-kappa B signaling pathway (c-FLIP, MIP1β) were significantly different between osteoporosis patients and control samples. The analysis of immune cell infiltration revealed that monocytes, activated CD4 memory T cells, and memory and naïve B cells may be related to the occurrence and development of OP.ConclusionsWe identified six novel OP diagnostic marker genes and ten OP-hub genes. These genes can be used to improve the prognostic of OP and to identify potential relationships between the immune microenvironment and OP. Our research will provide insights into the potential therapeutic targets and pathogenesis of osteoporosis.

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Tereticornate A suppresses RANKL-induced osteoclastogenesis via the downregulation of c-Src and TRAF6 and the inhibition of RANK signaling pathways

Cited by 10 publications

References 35 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

Allolobophora caliginosa coelomic fluid and extract alleviate glucocorticoid-induced osteoporosis in mice by suppressing oxidative stress and regulating osteoblastic/osteoclastic-related markers

Prognostic analysis and validation of diagnostic marker genes in patients with osteoporosis

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