Ginsenoside Rh2 inhibits osteoclastogenesis through down-regulation of NF-κB, NFATc1 and c-Fos

Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, South Korea.
Bone (Impact Factor: 3.97). 03/2012; 50(6):1207-13. DOI: 10.1016/j.bone.2012.03.022
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Ginsenoside Rh2 is one of the most active components of red ginseng, controlling cancer and other metabolic diseases including osteoclast differentiation. However, the molecular mechanism underlying the inhibition of osteoclast differentiation by ginsenoside Rh2 remains poorly understood. In the present study, it was found that ginsenoside Rh2 suppressed osteoclast differentiation from bone marrow macrophages (BMMs) treated with receptor activator of nuclear factor κB ligand (RANKL) without any cytotoxicity. Ginsenoside Rh2 significantly reduced RANKL-induced expression of transcription factors, c-Fos and nuclear factor of activated T-cells (NFATc1), as well as osteoclast markers, TRAP and OSCAR. In defining the signaling pathways, ginsenoside Rh2 was shown to moderately inhibit NF-κB activation and ERK phosphorylation in response to RANKL stimulation in BMM cells without any effect on p38 and c-Jun N-terminal kinase (JNK). Finally, ginsenoside Rh2 blocked osteoporosis in vivo as confirmed by restored bone mineral density (BMD) and other markers associated osteoclast differentiation. Hence, it is suggested that ginsenoside Rh2 could suppress RANKL-induced osteoclast differentiation in vitro and in vivo through the regulation of c-Fos and NFATc1 expressions, not excluding the involvement of NF-κB and ERK. Ginsenoside Rh2 is also suggested to be developed as a therapeutic drug for prevention and treatment of osteoporosis.

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    • "In addition to NF-κB pathway, three well-known MAPKs (ERK, JNK, and p38) are also activated by RANKL stimulation and play important roles in osteoclast differentiation. Previous studies by our and other groups have demonstrated that the inhibition of ERK activation suppresses osteoclast formation (He et al., 2012; Kim et al., 2007; 2014a). In the present study, capric acid specifically blocked the phosphorylation of ERK by RANKL, whereas it did not affect the activation of JNK and p38. "
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    ABSTRACT: Fatty acids, important components of a normal diet, have been reported to play a role in bone metabolism. Osteoclasts are bone-resorbing cells that are responsible for many bone-destructive diseases such as osteoporosis. In this study, we investigated the impact of a medium-chain fatty acid, capric acid, on the osteoclast differentiation, function, and survival induced by receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (MCSF). Capric acid inhibited RANKL-mediated osteoclastogenesis in bone marrow-derived macrophages and suppressed RANKL-induced IkappaBalpha phosphorylation, p65 nuclear translocation, and NF-kappaB transcriptional activity. Capric acid further blocked the RANKL-stimulated activation of ERK without affecting JNK or p38. The induction of NFATc1 in response to RANKL was also attenuated by capric acid. In addition, capric acid abrogated M-CSF and RANKLmediated cytoskeleton reorganization, which is crucial for the efficient bone resorption of osteoclasts. Capric acid also increased apoptosis in mature osteoclasts through the induction of Bim expression and the suppression of ERK activation by M-CSF. Together, our results reveal that capric acid has inhibitory effects on osteoclast development. We therefore suggest that capric acid may have potential therapeutic implications for the treatment of bone resorption-associated disorders.
    Molecules and Cells 08/2014; 37(8). DOI:10.14348/molcells.2014.0153 · 2.09 Impact Factor
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    • "In CIA joints, the decrease in number of Th17 cells, seems to have resulted in a reduction in TRAP(+) osteoclasts. The inhibitory effect of RGE on osteoclastogenesis in vitro was previously reported by He et al. [33]. They demonstrated that ginsenoside Rh2, a component of red ginseng, suppressed osteoclast differentiation by inhibiting RANKL-induced c-fos and NFATc1 expression. "
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    ABSTRACT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation. Red ginseng is a steamed and dried Panax ginseng C.A. Meyer, which has been used as alternative medicine for thousands of years. This study was undertaken to investigate the effects of red ginseng extracts (RGE) on autoimmune arthritis in mice and humans and to delineate the underlying mechanism. RGE was orally administered three times a week to mice with arthritis. Oral administration of RGE markedly ameliorated clinical arthritis score and histologically assessed joint inflammation in mice with CIA. A significant reduction in STAT3 phosphorylation and a decrease in the number of Th17 cells were observed with RGE treatment. There was also a marked reduction in RANKL-induced osteoclastogenesis with treatment of RGE. The inhibitory effect of RGE on Th17 differentiation and osteoclastogenesis observed in mice was also confirmed in the subsequent experiments performed using human peripheral blood mononuclear cells. Our findings provide the first evidence that RGE can regulate Th17 and reciprocally promote Treg cells by inhibiting the phosphorylation of STAT3. Therefore, RGE can ameliorate arthritis in mice with CIA by targeting pathogenic Th17 and osteoclast differentiation, suggesting a novel therapy for treatment of RA.
    Mediators of Inflammation 07/2014; 2014:351856. DOI:10.1155/2014/351856 · 3.24 Impact Factor
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    • "KRG consists of various ginsenoside components including Rg1, Rb1, Rc, Rf, Re, Rb2, and Rg2, which may differentially regulate signaling pathways and PAI-1 expression. Recent reports suggested an array of different effects of individual ginsenosides on JNK activity in many cell types; i.e., no effects by Rh2 [32], inhibition by Rb1 [33], and activation by Rg3 or CK [34,35]. Interestingly, we did not observe any effects of Rb1 and Rg1 on PAI-1 activity in rat primary astrocytes. "
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    ABSTRACT: Korean Red Ginseng (KRG) is an oriental herbal preparation obtained from Panax ginseng Meyer (Araliaceae). To expand our understanding of the action of KRG on central nervous system (CNS) function, we examined the effects of KRG on tissue plasminogen activator (tPA)/plasminogen activator inhibitor-1 (PAI-1) expression in rat primary astrocytes. KRG extract was treated in cultured rat primary astrocytes and neuron in a concentration range of 0.1 to 1.0 mg/mL and the expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and reverse transcription-polymerase chain reaction. KRG extracts increased PAI-1 expression in rat primary astrocytes in a concentration dependent manner (0.1 to 1.0 mg/mL) without affecting the expression of tPA itself. Treatment of 1.0 mg/mL KRG increased PAI-1 protein expression in rat primary astrocytes to 319.3±65.9% as compared with control. The increased PAI-1 expression mediated the overall decrease in tPA activity in rat primary astrocytes. Due to the lack of PAI-1 expression in neuron, KRG did not affect tPA activity in neuron. KRG treatment induced a concentration dependent activation of PI3K, p38, ERK1/2, and JNK in rat primary astrocytes and treatment of PI3K or MAPK inhibitors such as LY294002, U0126, SB203580, and SP600125 (10 μM each), significantly inhibited 1.0 mg/mL KRG-induced expression of PAI- 1 and down-regulation of tPA activity in rat primary astrocytes. Furthermore, compound K but not other ginsenosides such as Rb1 and Rg1 induced PAI-1 expression. KRG-induced up-regulation of PAI-1 in astrocytes may play important role in the regulation of overall tPA activity in brain, which might underlie some of the beneficial effects of KRG on CNS such as neuroprotection in ischemia and brain damaging condition as well as prevention or recovery from addiction.
    Journal of ginseng research 10/2013; 37(4):401-12. DOI:10.5142/jgr.2013.37.401 · 2.82 Impact Factor
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