NVP-BHG712 alleviates ovariectomy-induced osteoporosis by modulating osteoclastogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE261350 | GEO | 2024/12/01
REPOSITORIES: GEO
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Project description:NVP-BHG712 alleviates ovariectomy-induced osteoporosis by modulating osteoclastogenesis
| PRJNA1086539 | ENA
Project description:A rapidly aging society and longer life expectancy are causing osteoporosis to become a global epidemic. Over the last five decades, a number of drugs aimed at reducing bone resorption or restoring bone mass have been developed, but their efficacy and safety are limited. Icaritin (ICT) is a natural compound extracted from anti-osteoporosis herb Epimedium spp. and has been shown to inhibit osteoclast differentiation. However, the molecular mechanism by which ICT weaken RANKL-induced osteoclast differentiation has not been completely investigated. Here, we evaluated the anti-osteoclastogenic effect of ICT in vitro and the potential drug candidate for treating osteoporosis in vivo. In vitro study, ICT was found to inhibit osteoclast formation and bone resorption function via downregulating transcription factors activated T cell cytoplasm 1 (NFATc1) and c-fos, which further downregulate osteoclastogenesis-specific gene. In addition, the enhanced mitochondrial mass and function required for osteoclast differentiation was mitigated by ICT. The histomorphological results from an in vivo study showed that ICT attenuated the bone loss associated with ovariectomy (OVX). Based on these results, we propose ICT as a promising new drug strategy for osteoporosis that inhibits osteoclast differentiation.
| S-EPMC10599742 | biostudies-literature
Project description:Osteoporosis is a common aging-related metabolic disease that mainly occurs in older adults and postmenopausal women. Despite advances in anti-osteoporosis treatment, outcomes remain unsatisfactory due to detrimental side effects. BCI hydrochloride (BCI), a selective dual-specificity phosphatase 6 (DUSP6) inhibitor, is associated with multiple cellular functions, including inhibiting tumor growth and macrophage inflammation; however, its role in regulating osteoclast differentiation remains unknown. Here, we revealed that treatment with BCI attenuated RANKL-mediated osteoclast differentiation in vitro and alleviated ovariectomy-induced osteoporosis without obvious toxicity. Specifically, BCI disrupted F-actin ring formation and bone-resorption activity and decreased osteoclast-specific gene and protein levels in a dose-dependent manner. KEGG pathway analysis, GSEA based on transcriptome sequencing, and western blot results suggested that BCI inhibited RANKL-induced osteoclastogenesis by restraining STAT3 and NF-κB signaling and attenuating NF-κB/p65 interaction with NFATc1. These results revealed that BCI treatment prevented postmenopausal osteoporosis and might represent an effective approach for treating osteoporosis.
| S-EPMC8596812 | biostudies-literature
Project description:Bone marrow derived macrophages (BMM) from Notch2tm1.1Ecan, harboring a NOTCH2 gain-of-function mutation, and control mice were cultured with macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL). Bulk RNA-Seq revealed enhanced cell metabolism, aerobic respiration, and mitochondrial function, all associated with osteoclastogenesis, in Notch2tm1.1Ecan cells. Single cell RNA-Seq data of BMMs treated with M-CSF or M-CSF and RANKL for 3 days identified 11 well-defined cellular clusters. There was an increased number of cells expressing gene markers associated with the osteoclast and with related clusters in Notch2tm1.1Ecan than in control BMMs.
2024-01-03 | GSE248137 | GEO
Project description:Bone marrow derived macrophages (BMM) from Notch2tm1.1Ecan, harboring a NOTCH2 gain-of-function mutation, and control mice were cultured with macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL). Bulk RNA-Seq revealed enhanced cell metabolism, aerobic respiration, and mitochondrial function, all associated with osteoclastogenesis, in Notch2tm1.1Ecan cells. Single cell RNA-Seq data of BMMs treated with M-CSF or M-CSF and RANKL for 3 days identified 11 well-defined cellular clusters. There was an increased number of cells expressing gene markers associated with the osteoclast and with related clusters in Notch2tm1.1Ecan than in control BMMs.
2024-01-03 | GSE248138 | GEO
Project description:Osteoporosis is a common bone disease that has become a serious public health problem with the aging of population. Osteoclasts are the only cells in body that can resorb bone, whose dysfunction is closely related to osteoporosis. Pyruvate kinase M2 (PKM2) is one of the essential rate-limiting enzymes in the process of glycolysis. This study aimed to elucidate the role of PKM2 in osteoclastogenesis and bone resorption. Bone marrow-derived macrophages (BMMs) were transfected with adenovirus to knock down the expression of PKM2 gene or treated with the PKM2 activators TEPP-46 and DASA-58. Osteoclast formation was detected by TRAP staining, osteoclast-specific gene and protein expression was detected by RT-qPCR and Western blotting, and the effect of DASA-58 on osteoclast gene expression at the transcriptional level was examined by RNA-seq. The results showed that knockdown of PKM2 by adenoviral transfection or treatment with PKM2 activators TEPP-46 and DASA-58 inhibited osteoclast differentiation and suppressed the expression of osteoclast-associated genes in BMMs. Furthermore, PKM2 activators TEPP-46 and DASA-58 could inhibit several signaling pathways in osteoclasts; knockdown of PKM2 or treatment with PKM2 activators TEPP-46 and DASA-58 both affected osteoclast precursor cell fusion by inhibiting the expression of osteoclast stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP). Therefore, PKM2 is closely related to osteoclast differentiation and formation, and the development of new therapeutic strategies targeting the PKM2 gene in osteoclasts may be feasible for the prevention and treatment of osteoporosis.
2025-03-17 | GSE188963 | GEO
Project description:In this study, we investigated the mechanisms by which puerarin alleviates osteoclast-related loss of bone mass in ovariectomy (OVX)-induced osteoporosis model mice. Puerarin-treated OVX mice exhibited higher bone density, fewer tartrate-resistant acid phosphatase (TRAcP)-positive osteoclasts, and levels of lower reactive oxygen species (ROS) within bone tissues than vehicle-treated OVX mice. Puerarin suppressed in vitro osteoclast differentiation, hydroxyapatite resorption activity, and expression of osteoclastogenesis-related genes, such as NFATc1, MMP9, CTSK, Acp5 and c-Fos, in RANKL-induced bone marrow macrophages (BMMs) and RAW264.7 cells. It also reduced intracellular ROS levels by suppressing expression of TRAF6 and NADPH oxidase 1 (NOX1) and increasing expression of antioxidant enzymes such as heme oxygenase-1 (HO-1). Puerarin inhibited TRAF6/ROS-dependent activation of the MAPK and NF-κB signaling pathways in RANKL-induced RAW264.7 cells, and these effects were partially reversed by HO-1 silencing or TRAF6 overexpression. These findings suggest puerarin alleviates loss of bone mass in the OVX-model mice by suppressing osteoclastogenesis via inhibition of the TRAF6/ROS-dependent MAPK/NF-κB signaling pathway.
| S-EPMC7695364 | biostudies-literature
Project description:Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel post-transcriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.
2025-03-27 | GSE279363 | GEO
Project description:Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel post-transcriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.
2025-03-27 | GSE279361 | GEO
Project description:Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4-acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel post-transcriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.
2025-03-27 | GSE280178 | GEO