Asiatic Acid Inhibits OVX-Induced Osteoporosis and Osteoclastogenesis Via Regulating RANKL-Mediated NF-κb and Nfatc1 Signaling Pathways

Hong, Guoju; Zhou, Lin; Han, Xianlin; Sun, Ping; Chen, Zhenqiu; He, Wei; Tickner, Jennifer; Chen, Leilei; Shi, Xiuquan; Xu, Jiake

doi:10.3389/fphar.2020.00331

Cited by 24 publications

(21 citation statements)

References 29 publications

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“…These results are in line with the work carried out by Lin et al., and Zaman et al., [ 40 , 42 ]. Further, the downregulation of NFATc1 by LG in the present study is in accordance with the earlier reported work of Hong et al., [ 43 ]. In addition, it has also been reported that NFATc1 upregulates various pro-apoptotic genes including FasL, TNF-α, etc [ 44 ].…”

Section: Discussionsupporting

confidence: 94%

Molecular insights for an anti-osteoporotic properties of Litsea glutinosa on Saos-2 cells: An in-vitro approach

Changani

Parikh

2022

Journal of Ayurveda and Integrative Medicine

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Osteoporosis is a skeletal disease that is identified by the deterioration of micro-architecture of bone tissue, leading to enhanced bone brittleness and a consequential increase in fracture threat. There are many treatments available for osteoporosis such as bisphosphonate therapy, hormonal replacement therapy, herbal therapy etc. For decades, there are several herbs that are attributed to have anti-osteoporotic effects however the candidate genes involved in it remained unknown. In line with this, the present study is focused to elucidate the anti-osteoporotic property of Litsea glutinosa (LG). To understand the proliferative effect and identify involved players, gene expression was studied on the Saos-2 osteocytes in-vitro . The expression profile of candidate genes involved in different signaling pathways such as Egr-2, RUNX2, MAPK3, NFATc1, CREB, ERβ, along with proliferation and apoptotic markers in osteoporosis were selected for the study. The gene expression profile demonstrated a significant up-regulation of Egr-2, RUNX2, MAPK3, CREB, EBβ in the range of 1.5–2.2 folds, whereas NFATc1 was found to be down-regulated up to 0.4 times compared to control when treated with 250 μg/mL of LG. Besides this, anti-apoptosis effect of LG was also supported by flow cytometry results which also proved that LG induces proliferation and inhibits apoptosis, suggesting the proliferative role of LG. In conclusion, the present study gathers the potency of LG extract for its proliferative and anti-apoptotic effect on Saos-2 osteocytes and opens a new avenue for detailing the mechanistic actions of it on mitigating the pathophysiology of osteoporosis.

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Section: Discussionsupporting

confidence: 94%

Molecular insights for an anti-osteoporotic properties of Litsea glutinosa on Saos-2 cells: An in-vitro approach

Changani

Parikh

2022

Journal of Ayurveda and Integrative Medicine

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“…(H) The protein expression of c-fos and NFATc1 was substantially lower in the celastrol-treated group than in the RANKL-induced group after 1, 3, or 5 days, respectively. All experiments were carried out three times, and all data are showed as the means ± SD; *p < 0.05, **p < 0.01. pathways in bone metabolism therapy (Hong et al, 2020;Zhu et al, 2021). Although traditional natural medicine therapies have been around for thousands of years, their active ingredients and mechanism of action remain undefined.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, new therapeutic drugs are urgently needed for the clinical treatment of osteoclast-related osteolytic diseases. Recent studies have shown the potential use of natural medicines targeting multiple pathways in bone metabolism therapy ( Hong et al, 2020 ; Zhu et al, 2021 ). Although traditional natural medicine therapies have been around for thousands of years, their active ingredients and mechanism of action remain undefined.…”

Section: Discussionmentioning

confidence: 99%

Celastrol Attenuates RANKL-Induced Osteoclastogenesis in vitro and Reduces Titanium Particle-Induced Osteolysis and Ovariectomy-Induced Bone Loss in vivo

Chen

et al. 2021

Front. Pharmacol.

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Excessive bone resorption by osteoclasts contributes significantly to osteoclast-related diseases such as periprosthetic osteolysis and osteoporosis. Osteolysis in a titanium particle-induced calvarial model and bone loss in an ovariectomized mice model occurred similarly to those in humans; thus, these models can be used to evaluate potential therapies for aseptic prosthetic loosening and osteoporosis. Celastrol, which is extracted from the seeds of the genus Tripterygium, has been thoroughly investigated for its anti-inflammatory and anti-cancer pharmacological effects. However, the mechanisms involving bone metabolism by which celastrol inhibits osteoclastogenesis are not yet fully understood. We demonstrated that celastrol inhibited the receptor activator of nuclear factor κB ligand-induced osteoclastogenesis and the bone resorptive function of osteoclasts in vitro by inhibiting the activation of transforming growth factor β-activated kinase 1-mediated NF-κB and mitogen-activated protein kinase signaling pathways and downregulating osteoclastogenesis marker-related genes. Furthermore, celastrol was also shown to be beneficial in both the titanium particle-induced osteolysis calvarial and the murine ovariectomy-induced bone loss. Collectively, our results suggested that celastrol is promising for the prevention of aseptic prosthetic loosening and osteoporosis in the treatment of osteolytic diseases induced by disrupted osteoclast formation and function.

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“…Additionally, multiple studies have shown that there was a substantial correlation between the pharmacological effects of asiatic acid and the Akt signaling pathway ( Ren et al, 2016 ; Hao et al, 2018 ; Gou et al, 2020 ), including the biological basis of asiatic acid in the degradation of articular cartilage treatment ( Liu et al, 2020 ). Recently, asiatic acid has been shown to effectively inhibit osteoclast differentiation and alleviate osteoporosis through the TGF- β /NF-κB/NFATc1 pathways ( Huang et al, 2019 ; Hong et al, 2020 ). However, the mechanism by which asiatic acid affects bone metabolism has not been thoroughly elucidated to date.…”

Section: Introductionmentioning

confidence: 99%

Asiatic Acid Attenuates Osteoporotic Bone Loss in Ovariectomized Mice Through Inhibiting NF-kappaB/MAPK/ Protein Kinase B Signaling Pathway

et al. 2022

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Osteoporosis is a condition associated with osteolytic bone disease that is primarily characterized by inordinate osteoclast activation. Protein kinase B (Akt) pathways activated by receptor activator of nuclear factor kappa-B ligand (RANKL) are essential for osteoclastogenesis. Asiatic acid (AA) is a natural pentacyclic triterpenoid compound extracted from a traditional Chinese herb that exhibits a wide range of biological activities. AA has been found to alleviate the hypertrophic and fibrotic phenotype of chondrocytes via the Akt signaling pathway. In this study, we investigated whether AA alleviated bone loss by inhibiting the Akt signaling pathway during osteoclastogenesis and its effect on osteoblasts. The effect of AA cytotoxicity on mouse bone marrow-derived macrophages/monocytes (BMMs) was evaluated in vitro using a Cell Counting Kit-8 assay. The effects of AA on osteoclast differentiation and function were detected using tartrate-resistant acid phosphatase (TRAP) staining and a pit formation assay. A Western blot and qRT-PCR were conducted to evaluate the expression of osteoclast-specific genes and protein signaling molecules. In addition, alkaline phosphatase and alizarin red staining were performed to assess osteoblast differentiation and mineralization. The bone protective effect of AA was investigated in vivo using ovariectomized mice. we found that AA could dose-dependently inhibit RANKL-induced osteoclastogenesis. Moreover, the pit formation assay revealed that osteoclast function was suppressed by treatment with AA. Moreover, the expression of osteoclast-specific genes was found to be substantially decreased during osteoclastogenesis. Analysis of the molecular mechanisms showed that AA could inhibit NF-kappaB/MAPK/Akt signaling pathway, as well as the downstream factors of NFATc1 in the osteoclast signaling pathway activated by RANKL. However, AA did not significantly promote osteoblast differentiation and mineralization. The in vivo experiments suggested that AA could alleviate ovariectomy-induced bone loss in ovariectomized mice. Our results demonstrate that AA can inhibit osteoclastogenesis and prevent ovariectomy-induced bone loss by inhibiting the NF-kappaB/MAPK/Akt signaling pathway. The discovery of the new molecular mechanism that AA inhibits osteoclastogenesis provides essential evidence to support the use of AA as a potential drug for the treatment of osteoclast-related diseases.

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Asiatic Acid Inhibits OVX-Induced Osteoporosis and Osteoclastogenesis Via Regulating RANKL-Mediated NF-κb and Nfatc1 Signaling Pathways

Cited by 24 publications

References 29 publications

Molecular insights for an anti-osteoporotic properties of Litsea glutinosa on Saos-2 cells: An in-vitro approach

Molecular insights for an anti-osteoporotic properties of Litsea glutinosa on Saos-2 cells: An in-vitro approach

Celastrol Attenuates RANKL-Induced Osteoclastogenesis in vitro and Reduces Titanium Particle-Induced Osteolysis and Ovariectomy-Induced Bone Loss in vivo

Asiatic Acid Attenuates Osteoporotic Bone Loss in Ovariectomized Mice Through Inhibiting NF-kappaB/MAPK/ Protein Kinase B Signaling Pathway

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