Open Access

Ginsenoside Rb1 prevents steroid‑induced avascular necrosis of the femoral head through the bone morphogenetic protein‑2 and vascular endothelial growth factor pathway

  • Authors:
    • Junwu Ye
    • Daiqin Wei
    • Lin Peng
    • Tianmin Chang
  • View Affiliations

  • Published online on: August 6, 2019     https://doi.org/10.3892/mmr.2019.10553
  • Pages: 3175-3181
  • Copyright: © Ye et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

At present, the molecular mechanism underlying the protective effect of Ginsenoside Rb1 remains unclear. The present study was designed to investigate whether Ginsenoside Rb1 weakened the steroid‑induced avascular necrosis of the femoral head (SANFH) and to explore the possible mechanisms of the above effects. As a result, it was revealed that Ginsenoside Rb1 was protective against steroid‑induced avascular necrosis and inhibited serum osteocalcin in a rat model of SANFH. Ginsenoside Rb1 reduced inflammation, oxidative stress and bone cell apoptosis in a rat model of SANFH. Furthermore, Ginsenoside Rb1 attenuated trabecula parameters, total cholesterol and low density lipoprotein/high density lipoprotein in SANFH rat. Additionally, Ginsenoside Rb1 significantly reversed alkaline phosphatase and osteocalcin activities, vascular endothelial growth factor (VEGF) receptor, VEGF, Runt related transcription factor 2 (Runx2) and bone morphogenetic protein (BMP)‑2 protein expression in SANFH rat. Collectively, the present study demonstrated that Ginsenoside Rb1 attenuated SANFH through the VEGF/RUNX2/BMP‑2 signaling pathway.

Introduction

Steroid-induced avascular necrosis of the femoral head (SANFH) is caused by a variety of factors, including apoptosis, inflammation, reactive oxygen species and oxidative stress (1). SANFH is characterized by bone trabeculae and bone marrow necrosis (1). Cases of SANFH are increasing worldwide and patient outcomes are poor (2). Thus, developing strategies to effectively prevent and/or treat SANFH is of critical importance (2).

SANFH is defined by the interruption and impairment of blood supply to the femoral head, which triggers osteocyte and bone marrow necrosis (3). This leads to alterations in the structure of the femoral head, collapse and joint function disturbance. However, the pathogenesis of SANFH remains largely unclear (4). Clinically, femoral head necrosis can be divided into traumatic and non-traumatic types (4). The prolonged administration of hormones is a risk factor for non-traumatic femoral head necrosis (5).

Ginsenoside Rb1 is a dammarane-type triterpenoid saponin that is predominantly found in Panax plants, such as ginseng, Panax notoginseng and American ginseng (6). Panax plants are valuable Chinese herbal medicines with a long history of application (7). Ginsenoside Rb1 harbors a variety of pharmacological activities in the central nervous system, cardiovascular system and immune system, as well as anti-tumor, anti-hepatic ischemia-reperfusion injury, and hypoglycemic effects (7,8). Shen et al (9) reported that Ginsenoside Rb1 reduces fatty liver by activating adenosine monophosphate-activated protein kinase in obese rats. Wang et al (10) reported that Ginsenoside Rb1 inhibits free fatty acidinduced oxidative stress and inflammation in 3T3L1 adipocytes. The present study was designed to investigate whether Ginsenoside Rb1 weakened the steroid-induced avascular necrosis of the femoral head (SANFH) and to explore the possible mechanisms of the above effects.

Materials and methods

Animals, reagents and in vivo experiments

Adult male Sprague-Dawley rats (230–260 g; 6–9 weeks; n=30) were housed at 24±2°C and 55±2% humidity, with free access to food and water, and a 12-h light/dark cycle, at the Department of Laboratory Animal Science Affiliated to Southwest Medical University (Luzhou, China). All procedures were approved by the Ethical Committee of Animal Experimentation at Southwest Medical University.

Rats were randomly divided into three groups: i) Blank control group (sham; n=10); ii) model group (n=10); and iii) Ginsenoside Rb1 treatment group (n=10). Rats in the model and Ginsenoside Rb1 groups received intragluteal injections of 50 mg/kg dexamethasone twice per week for 6 weeks. After the induction of SANFH for 3 weeks, rats in the Ginsenoside Rb1 group received 200 mg/kg/week Ginsenoside Rb1 (Fig. 1A; Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd.) by oral gavage for 3 weeks (11). In the blank control and model groups, rats were given normal saline for 3 weeks by the same method.

ELISA

Following treatment with Ginsenoside Rb1, blood samples were collected under anesthesia (35 mg/kg of pentobarbital sodium) and centrifugated at 12,000 × g for 10 min at 4°C. Serum osteocalcin (OST; cat. no. H152), total cholesterol (cat. no. A111-1-1) and the ratio of low-density lipoprotein to high-density lipoprotein (LDL/HDL; cat. no. A113-1-1 and A112-1-1) were examined using ELISA (all from Nanjing Jiancheng Bioengineering Institute), according to the manufacturer's protocol. Absorbance was measured at 450 nm with a microplate reader (Bio-Rad Laboratories).

Histopathological examination

Following treatment with Ginsenoside Rb1, rats were sacrificed by decapitation under anesthesia (35 mg/kg pentobarbital sodium). Femur samples were obtained and fixed in 10% buffered neutral formalin solution for 3–4 days at room temperature and decalcified in 10% EDTA, 0.1 M phosphate buffer. Tissue was dehydrated with ethanol, embedded in paraffin and cut into 4 µm thick sections. Sections were stained with hematoxylin for 10 min at room temperature, and rinsed with running water for 15 min. Sections were then stained with eosin for 30 sec at room temperature, and double distilled water was used to wash the sections. The sections were dehydrated using 100% ethanol for 1 min at room temperature, cleared in xylene and sealed with neutral balsam. Sections were observed using a Zeiss Axioplan 2 light microscope (magnification, ×10; Carl Zeiss AG).

Inflammatory factor, oxidative stress, alkaline phosphatase (ALP), OST and caspase-3 activity analysis

Femoral heads were washed in PBS and lysed with RIPA buffer (Beyotime Institute of Biotechnology) on ice for 1 h. The supernatant was collected by centrifugation at 12,000 × g for 10 min at 4°C. For caspase-3 activity, samples were incubated with specific colorimetric peptide substrates (Ac-DEVD-pNA; Beyotime Institute of Biotechnology) for 1 h at 37°C, and the absorbance was measured at 405 nm with a microplate reader (Eppendorf). ALP (cat. no. A059-2-2), OST (cat. no. H152), p65 (cat. no. H202), tumor necrosis factor (TNF)-α (cat. no. H052), interleukin (IL)-1β (cat. no. H002), IL-6 (cat. no. H007), malondialdehyde (MDA; cat. no. A003-1-2), superoxide dismutase (SOD; cat. no. A001-3-2), chloramphenicol acetyltransferase (CAT; cat. no. A007-1-1) and glutathione peroxidase (GSH-PX; cat. no. A005-1-2) expression was measured using ELISA kits (all from Nanjing Jiancheng Bioengineering Institute), according to the manufacturer's protocol. Absorbance was measured at 450 nm with a microplate reader (Eppendorf).

Western blot analysis

Femoral heads were washed in PBS and lysed with RIPA buffer on ice for 1 h. The supernatant was collected by centrifugation at 12,000 × g for 10 min at 4°C and protein concentration was determined with a bicinchoninic acid protein assay. Proteins (50 µg/lane) were separated by 8–10% SDS-PAGE and transferred to polyvinylidene fluoride membranes. Membranes were blocked with 5% non-fat milk in TBST for 1 h at 37°C and incubated with anti-apoptosis regulator BAX (Bax; 1:500; cat. no. sc-20067; Santa Cruz Biotechnology, Inc.), anti-cellular tumor antigen p53 (p53; 1:500; cat. no. sc-47698; Santa Cruz Biotechnology, Inc.), anti-vascular endothelial growth factor (VEGF) receptor (VEGFR; 1:2000; cat. no. 2479; Cell Signaling Technology, Inc.), anti-VEGF (1:500; cat. no. sc-7269; Santa Cruz Biotechnology, Inc.), anti-Runt-related transcription factor 2 (RUNX2; 1:500; cat. no. sc-390715; Santa Cruz Biotechnology, Ltd.), anti-bone morphogenetic protein 2 (BMP2; 1:500; cat. no. sc-137087; Santa Cruz Biotechnology, Ltd.) and anti-GAPDH (1:2,000; cat. no. sc-69778; Santa Cruz Biotechnology, Ltd.) primary antibodies at 4°C overnight. Following washing with TBST, the membranes were incubated with a goat anti-rabbit IgG antibody conjugated to horseradish peroxidase (1:5,000; cat. no. sc-2004; Santa Cruz Biotechnology, Inc.) for 1 h at 37°C. Membranes were visualized using BeyoECL Moon reagent (Beyotime Institute of Biotechnology) and analyzed with Quantity One software (version 3.0; Bio-Rad Laboratories, Inc.).

Statistical analysis

All data were expressed as the mean ± standard deviation and analyzed using SPSS 17.0 (SPSS, Inc.). A minimum of three independent experiments were carried out and were analyzed by one-way analysis of variance and Tukey's post hoc test. using SPSS 17.0. P<0.05 was considered to indicate a statistically significant difference.

Results

Ginsenoside Rb1 improves ALP and OST activities in the SANFH rat model

To assess the effects of Ginsenoside Rb1 on ALP and OST activity in the SANFH rat model, ALP and OST activities were determined using ELISA kits. Firstly, H&E staining showed that the bone cell number was reduced in SANFH rats, compared with the control group (Fig. 1B). Ginsenoside Rb1 appeared to increase the number of bone cells, compared with the untreated rat model (Fig. 1B). Furthermore, ALP (Fig. 1C) and OST (Fig. 1D) activity in the rat model was significantly decreased, compared with the control group. Ginsenoside Rb1 administration significantly increased ALP and OST activity, compared with untreated model rats.

Protective effects of Ginsenoside Rb1 on avascular necrosis of the SANFH rat model

Serum OST expression was significantly decreased in the SANFH model group, compared with the control (Fig. 2A). In addition, the total cholesterol (Fig. 2B) and LDL/HDL ratio (Fig. 2C) were higher in the model group, compared with the control. Treatment with Ginsenoside Rb1 significantly elevated serum OST expression, and reduced total cholesterol and LDL/HDL ratio in SANFH rats.

Protective effects of Ginsenoside Rb1 on inflammation of the SANFH rat model

To assess the effects of Ginsenoside Rb1 on inflammation in SANFH, p65, TNF-α, IL-1β and IL-6 expression was determined using ELISA kits. p65 (Fig. 3A), TNF-α (Fig. 3B), IL-1β (Fig. 3C) and IL-6 (Fig. 3D) expression was significantly upregulated in SANFH model rats, compared with the control group. Treatment with Ginsenoside Rb1 significantly reduced p65, TNF-α, IL-1β and IL-6 expression in SANFH rats compared with model rats.

Ginsenoside Rb1 reduces oxidative stress in SANFH rats

Next, it was demonstrated that MDA expression was increased (Fig. 4A), whereas SOD (Fig. 4B), CAT (Fig. 4C) and GSH-PX (Fig. 4D) expression was decreased in the model group, compared with the control. Consistently, treatment with Ginsenoside Rb1 significantly reduced MDA levels, and increased SOD, CAT and GSH-PX levels in SANFH rats, compared with the model group.

Ginsenoside Rb1 reduces bone cell death in a rat model of SANFH

The protective effects of Ginsenoside Rb1 against apoptosis in the femoral head were also explored. Specifically, Bax and p53 protein expression and caspase-3 activity were measured by western blotting (Fig. 5A). It was demonstrated that p53 (Fig. 5B), Bax (Fig. 5C) and caspase-3 (Fig. 5D) protein expression was significantly increased in SANFH rats, compared with the control group. Treatment with Ginsenoside Rb1 significantly reduced the induction of Bax, p53 and caspase-3 protein expression in SANFH rats.

Ginsenoside Rb1 increases VEGF and VEGFR expression

Western blotting was also used to determine whether Ginsenoside Rb1 exerted protective effects on VEGFR and VEGF expression (Fig. 6A). VEGF (Fig. 6B) and VEGFR (Fig. 6C) protein expression was significantly suppressed in the model group, compared with controls. Administration of Ginsenoside Rb1 significantly induced VEGFR and VEGF protein expression in SANFH rats, compared with the untreated model group.

Ginsenoside Rb1 on RUNX2 and BMP-2 protein expression in a rat model

Finally, the protein expression of RUNX2 and BMP-2 was examined by western blot analysis (Fig. 7A). It was revealed that RUNX2 (Fig. 7B) and BMP-2 (Fig. 7C) protein expression in SANFH rats was lower than that of control group. Treatment with Ginsenoside Rb1 significantly induced RUNX2 and BMP-4 protein expression in SANFH rats, compared with SANFH model group.

Discussion

Hyperlipidemia manifests in SANFH throughout the whole course of the disease (12). Reduced osteogenic differentiation slows the reparative process and accelerates femoral head necrosis (13). In addition, hormone administration results in hyperlipidemia, thrombosis and bone tissue ischemia (14). Together, this leads to the development of SANFH. In the present study, Ginsenoside Rb1 was demonstrated to be protective against steroid-induced avascular necrosis, which inhibited serum OST expression, reduced oxidative stress and inhibited bone cell apoptosis in a rat model of avascular necrosis. Similar to the results of the present study, Xiang et al (15) reported that Ginsenoside Rb1 inhibits osteoarthritis by downregulating Notch signaling, and Zhu et al (16) demonstrated that Ginsenoside Rb1 alleviates aluminum chloride-induced rat osteoblast dysfunction.

Organisms would induce a repair response following SANFH (17). The head of the femur begins to repair from the edge of the sequestrum and the surrounding living tissues (18). It is represented as revascularization, osteogenesis and absorption of dead bones. VEGF plays an important role in osteogenesis by promoting angiogenesis and inhibiting the apoptosis of chondrocytes and osteoblasts to affect osteogenesis by means of promoting bone turnover (19). These results indicate that Ginsenoside Rb1 significantly induces VEGFR and VEGF protein expression in SANFH rat. Lan et al (20) has reported that Ginsenoside Rb1 prevents homocysteine-induced dysfunction through via the VEGF/p38MAPK pathway.

BMP plays an essential role in bone growth and wound repair. Active mesenchymal cells are the target cells of BMP (21). Under the induction of BMP, muscular and perivascular mesenchymal cells can be differentiated into osteocytes, a process that is specific and irreversible (22). Recent studies have suggested that BMP-2 may first combine with and activate Type II and I receptors on the surface of the membrane (23). Secondly, intracellular signal transduction pathways of Smad may then be activated to induce the transcription of intranuclear target genes and protein expressions (21). Novel research has suggested that BMP-2 is the most representative in BMP family, with relatively high contents (23). Furthermore, osteogenic activity is relatively high and potent; separation and purification are relatively easy. Taken together, these findings confirm that Ginsenoside Rb1 significantly induced BMP2 protein expression in SANFH rats. Zhu et al (16) reported that Ginsenoside Rb1 alleviates aluminum chloride-induced rat osteoblast dysfunction through BMP-2 expression.

Runx2 is affected both by positive effects during osteoblast differentiation from marrow stroma cells and by negative modulation (24). The expression of Runx2 is upregulated after activation, thereby promoting the production of osteoblasts (25), which is quite significant for the early repair of SANFH. However, the activities of Runx2 are inhibited by peroxisome proliferator-activated receptor γ, whose high expression can inhibit the expression of Runx2 (26). Thus, the differentiation from bone marrow stromal cells to osteoblasts is reduced while differentiation to adipocytes is increased (27). This change will trigger worse femoral head necrosis. Taken together, the above findings illustrate that Ginsenoside Rb1 significantly induced RUNX2 protein expression in SANFH rats.

In conclusion, these outcomes indicate that Ginsenoside Rb1 exerts a positive protective effect on SANFH that is mediated by osteogenic differentiation targeted VEGFR/VEGF and RUNX2/BMP-4 signaling pathways (Fig. 8). Ginsenoside Rb1 may be a useful and novel protective drug for patients who require corticosteroid treatments and are at risk of developing SANFH.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Authors' contributions

TC designed the experiments. JY, DW and LP performed the experiments. JY and TC analyzed the data. TC wrote the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All procedures were approved by the Ethical Committee of Animal Experimentation at Southwest Medical University.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Seldes RM, Tan V, Duffy G, Rand JA and Lotke PA: Total knee arthroplasty for steroid-induced osteonecrosis. J Arthroplasty. 14:533–537. 1999. View Article : Google Scholar : PubMed/NCBI

2 

Moriya M, Uchiyama K, Takahira N, Fukushima K, Yamamoto T, Hoshi K, Itoman M and Takaso M: Evaluation of bipolar hemiarthroplasty for the treatment of steroid-induced osteonecrosis of the femoral head. Int Orthop. 36:2041–2047. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Nagasawa K, Tada Y, Koarada S, Tsukamoto H, Horiuchi T, Yoshizawa S, Murai K, Ueda A, Haruta Y and Ohta A: Prevention of steroid-induced osteonecrosis of femoral head in systemic lupus erythematosus by anti-coagulant. Lupus. 15:354–357. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

5 

Khatami PG, Soleimani A, Sharifi N, Aghadavod E and Asemi Z: The effects of high-dose vitamin E supplementation on biomarkers of kidney injury, inflammation, and oxidative stress in patients with diabetic nephropathy: A randomized, double-blind, placebo-controlled trial. J Clin Lipidol. 10:922–929. 2016. View Article : Google Scholar : PubMed/NCBI

6 

Bouchi R, Nakano Y, Fukuda T, Takeuchi T, Murakami M, Minami I, Izumiyama H, Hashimoto K, Yoshimoto T and Ogawa Y: Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: A randomized control trial. Endocr J. 64:269–281. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Sulaj A, Kopf S, Grone E, Gröne HJ, Hoffmann S, Schleicher E, Häring HU, Schwenger V, Herzig S, Fleming T, et al: ALCAM a novel biomarker in patients with type 2 diabetes mellitus complicated with diabetic nephropathy. J Diabetes Complications. 31:1058–1065. 2017. View Article : Google Scholar : PubMed/NCBI

8 

Bahmani F, Kia M, Soleimani A, Mohammadi AA and Asemi Z: The effects of selenium supplementation on biomarkers of inflammation and oxidative stress in patients with diabetic nephropathy: A randomised, double-blind, placebo-controlled trial. Br J Nutr. 116:1222–1228. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Shen L, Xiong Y, Wang DQ, Howles P, Basford JE, Wang J, Xiong YQ, Hui DY, Woods SC and Liu M: Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats. J Lipid Res. 54:1430–1438. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Wang M, Chen Y, Xiong Z, Yu S, Zhou B, Ling Y, Zheng Z, Shi G, Wu Y and Qian X: Ginsenoside Rb1 inhibits free fatty acidsinduced oxidative stress and inflammation in 3T3L1 adipocytes. Mol Med Rep. 16:9165–9172. 2017. View Article : Google Scholar : PubMed/NCBI

11 

Zhou F, Zhang P and Chen X, Yan J, Yao J, Yu Z and Chen X: Ginsenoside Rb1 protects the intestinal mucosal barrier following peritoneal air exposure. Exp Ther Med. 12:2563–2567. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Powell C, Chang C and Gershwin ME: Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clin Rev Allergy Immunol. 41:102–113. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Tian L, Wen Q, Dang X, You W, Fan L and Wang K: Immune response associated with Toll-like receptor 4 signaling pathway leads to steroid-induced femoral head osteonecrosis. BMC Musculoskelet Disord. 15:182014. View Article : Google Scholar : PubMed/NCBI

14 

Li J, Fan L, Yu Z, Dang X and Wang K: The effect of deferoxamine on angiogenesis and bone repair in steroid-induced osteonecrosis of rabbit femoral heads. Exp Biol Med (Maywood). 240:273–280. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Xiang Y, Zhao J, Zhao M and Wang K: Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer. Exp Ther Med. 15:3537–3543. 2018.PubMed/NCBI

16 

Zhu Y, Hu C, Zheng P, Miao L, Yan X, Li H, Wang Z, Gao B and Li Y: Ginsenoside Rb1 alleviates aluminum chloride-induced rat osteoblasts dysfunction. Toxicology. 368-369:183–188. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Yuan HF, Pan JF, Li S, Guo CA, Liu SH and Yan ZQ: Protective effects of total saponins of panax notoginseng on steroid-induced avascular necrosis of the femoral head in vivo and in vitro. Evid Based Complement Alternat Med. 2015:1656792015. View Article : Google Scholar : PubMed/NCBI

18 

Patil AS, Sable RB and Kothari RM: Occurrence, biochemical profile of vascular endothelial growth factor (VEGF) isoforms and their functions in endochondral ossification. J Cell Physiol. 227:1298–1308. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Seamon J, Wang X, Cui F, Keller T, Dighe AS, Balian G and Cui Q: Adenoviral delivery of the VEGF and BMP-6 genes to rat mesenchymal stem cells potentiates osteogenesis. Bone Marrow Res. 2013:7375802013. View Article : Google Scholar : PubMed/NCBI

20 

Lan TH, Xu DP, Huang MT, Song JX, Wu HL and Li M: Ginsenoside Rb1 prevents homocysteine-induced EPC dysfunction via VEGF.p38MAPK and SDF-1/CXCR4 activation. Sci Rep. 7:130612017. View Article : Google Scholar : PubMed/NCBI

21 

Matsumoto T, Yamada A, Aizawa R, Suzuki D, Tsukasaki M, Suzuki W, Nakayama M, Maki K, Yamamoto M, Baba K and Kamijo R: BMP-2 induced expression of Alx3 that is a positive regulator of osteoblast differentiation. PLoS One. 8:e687742013. View Article : Google Scholar : PubMed/NCBI

22 

Li H, Johnson NR, Usas A, Lu A, Poddar M, Wang Y and Huard J: Sustained release of bone morphogenetic protein 2 via coacervate improves the osteogenic potential of muscle-derived stem cells. Stem Cells Transl Med. 2:667–677. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Geng S, Sun B, Lu R and Wang J: Coleusin factor, a novel anticancer diterpenoid, inhibits osteosarcoma growth by inducing bone morphogenetic protein-2-dependent differentiation. Mol Cancer Ther. 13:1431–1441. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Mariscal-Munoz E, Costa CA, Tavares HS, Bianchi J, Hebling J, Machado JP, Lerner UH and Souza PP: Osteoblast differentiation is enhanced by a nano-to-micro hybrid titanium surface created by Yb:YAG laser irradiation. Clin Oral Investig. 20:503–511. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Martin A, Xiong J, Koromila T, Ji JS, Chang S, Song YS, Miller JL, Han CY, Kostenuik P, Krum SA, et al: Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association. Bone. 75:96–104. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Yang S, Xu H, Yu S, Cao H, Fan J, Ge C, Fransceschi RT, Dong HH and Xiao G: Foxo1 mediates insulin-like growth factor 1 (IGF1)/insulin regulation of osteocalcin expression by antagonizing Runx2 in osteoblasts. J Biol Chem. 286:19149–19158. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Zhu L and Xu PC: Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem Biophys Res Commun. 432:612–617. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October-2019
Volume 20 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Ye J, Wei D, Peng L and Chang T: Ginsenoside Rb1 prevents steroid‑induced avascular necrosis of the femoral head through the bone morphogenetic protein‑2 and vascular endothelial growth factor pathway. Mol Med Rep 20: 3175-3181, 2019.
APA
Ye, J., Wei, D., Peng, L., & Chang, T. (2019). Ginsenoside Rb1 prevents steroid‑induced avascular necrosis of the femoral head through the bone morphogenetic protein‑2 and vascular endothelial growth factor pathway. Molecular Medicine Reports, 20, 3175-3181. https://doi.org/10.3892/mmr.2019.10553
MLA
Ye, J., Wei, D., Peng, L., Chang, T."Ginsenoside Rb1 prevents steroid‑induced avascular necrosis of the femoral head through the bone morphogenetic protein‑2 and vascular endothelial growth factor pathway". Molecular Medicine Reports 20.4 (2019): 3175-3181.
Chicago
Ye, J., Wei, D., Peng, L., Chang, T."Ginsenoside Rb1 prevents steroid‑induced avascular necrosis of the femoral head through the bone morphogenetic protein‑2 and vascular endothelial growth factor pathway". Molecular Medicine Reports 20, no. 4 (2019): 3175-3181. https://doi.org/10.3892/mmr.2019.10553