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Desoxyrhapontigenin Inhibits RANKL‑Induced Osteoclast Formation and Prevents Inflammation‑Mediated Bone Loss

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Desoxyrhapontigenin Inhibits RANKL‑Induced Osteoclast Formation and Prevents Inflammation‑Mediated Bone Loss INTERNATIONAL JOURNAL OF MOleCular meDICine 42: 569-578, 2018 Desoxyrhapontigenin inhibits RANKL‑induced osteoclast formation and prevents inflammation‑mediated bone loss PHUONG THAO TRAN1, DONG-HWA PARK2, OKHWA KIM1, SEUNG-HAE KWON3, BYUNG-SUN MIN2 and JEONG-HYUNG LEE1 1Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24341; 2College of Pharmacy, Catholic University of Daegu, Hayang, Gyeongbuk 38430; 3Division of Bio-Imaging, Korea Basic Science Institute Chuncheon Center, Chuncheon, Gangwon-Do 24341, Republic of Korea Received November 6, 2017; Accepted March 15, 2018 DOI: 10.3892/ijmm.2018.3627 Abstract. Desoxyrhapontigenin (DRG), a stilbene compound mouse model. At the molecular level, DRG inhibited the from Rheum undulatum, has been found to exhibit various RANKL-induced activation of extracellular signal-regulated pharmacological activities, however, its impact on osteoclast kinase, the expression of c-Fos, and the induction of NFATc1, formation has not been investigated. The present study inves- a crucial transcription factor for osteoclast formation. DRG tigated the effect of DRG on receptor activator of nuclear decreased the expression levels of osteoclast marker genes, factor-κB ligand (RANKL)-induced osteoclast differen- including matrix metalloproteinase-9, tartrate-resistant acid tiation in mouse bone marrow macrophages (BMMs) and phosphatase and cathepsin K. In conclusion, these findings inflammation‑induced bone loss in vivo. BMMs or RAW264.7 suggested that DRG inhibited the differentiation of BMMs cells were treated with DRG, followed by an evaluation of into mature osteoclasts by suppressing the RANKL-induced cell viability, RANKL-induced osteoclast differentiation, activator protein-1 and NFATc1 signaling pathways, and actin-ring formation and resorption pits activity. The effects may be a potential candidate for treating and/or preventing of DRG on the RANKL-induced phosphorylation of MAPK osteoclast-associated diseases, including osteoporosis. and the expression of nuclear factor of activated T cells cyto- plasmic 1 (NFATc1) and c-Fos were evaluated using western Introduction blot analysis once the BMMs were exposed to RANKL and DRG. The expression levels of osteoclast marker genes Bone mass homeostasis is regulated by a delicate balance were also evaluated using western blot analysis and reverse between osteoclast-mediated bone degradation and transcription-quantitative polymerase chain reaction A lipo- osteoblast-induced bone formation, a process termed bone polysaccharide (LPS)-induced murine bone loss model was remodeling (1). Osteoclasts are large cells with multiple nuclei, used to evaluate the protective effect of DRG on inflamma- which form from hematopoietic progenitors of the mono- tion-induced bone-loss. The results demonstrated that DRG cyte/macrophage lineage. The cells are specialized in bone suppressed the RANKL-induced differentiation of BMMs resorption (2). Several pathological bone-related diseases, into osteoclasts, osteoclast actin-ring formation and bone including postmenopausal osteoporosis, rheumatoid arthritis, resorption activity in a dose-dependent manner. Furthermore, periodontitis and lytic bone metastasis, are associated with DRG significantly inhibited LPS-induced bone loss in a excessive bone breakdown by an increase in the number and activity of osteoclasts (3-5). Macrophage-colony stimulating factor (M‑CSF) and receptor activator of nuclear factor (NF)-κB ligand (RANKL) are two major cytokines, which regulate osteo- Correspondence to: Dr Byung-Sun Min, College of Pharmacy, Catholic University of Daegu, 13-13 Hayang-ro, Hayang, clast differentiation (6-8). M‑CSF is responsible for the Gyeongbuk 38430, Republic of Korea proliferation and survival of osteoclast precursors and stimu- E-mail: [email protected] lates the expression of receptor activator of NF-κB (RANK), a receptor for RANKL, with RANKL inducing osteoclast Dr Jeong-Hyung Lee, Department of Biochemistry, College of Natural differentiation (7). The binding of RANKL to its receptor, Sciences, Kangwon National University, 1 Gangwondaehak-gil, Chuncheon, Gangwon‑Do 24341, Republic of Korea RANK, triggers several downstream signaling pathways, E-mail: [email protected] including the p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-acti- Key words: desoxyrhapontigenin, stilbene, receptor activator of vated protein kinase (MAPK) and NF-κB pathways, which nuclear factor-κB ligand, osteoclastogenesis, bone resorption lead to the activation of c-Fos and nuclear factor of acti- vated T cells cytoplasmic 1 (NFATc1) (9-14). NFATc1, a master transcription factor of osteoclast formation, induces several genes responsible for osteoclast differentiation and 570 TRAN et al: DESOXYRHAPONTIGENIN INHIBITS OSTEOCLASTOGENESIS function, including matrix metalloproteinase-9 (MMP-9), and resveratrol (200 mg). Sub-fraction E2-1-4 was rechro- tartrate-resistant acid phosphatase (TRAP) and cathepsin K matographed on a silica gel column with CH2Cl2-MeOH-H2O (CtsK) (15,16). (5:1:1) to obtain DRG (500 mg). Fraction E3 was fractionated There are many natural compounds that can be exploited on a silica gel column using CHCl3-MeOH (20:1→0:1) as the in the development of novel drugs (17). Several compounds solvent system to obtain piceatannol (3 g). Sub-fraction E3-3 from natural products suppress osteoclast formation and was purified using high‑performance liquid chromatography function. These products have potential therapeutic value for with a stepwise gradient of H2O-MeOH (1:1→3:1) to yield bone-related diseases characterized by the hyperactivation resveratroloside (15 mg). The structures of the stilbene deriva- of osteoclast activity (18). Rheum undulatum is a perennial tives are shown in Fig. 1. The purity of these stilbenes was plant that belongs to the Polygonaceae family and is mainly assessed using 1H and 13C nuclear magnetic resonance spectra. distributed in Korea. The rhizomes of R. undulatum and other The spectra revealed signals with a high level of purity with Rheum species, commonly known as rhubarb, have been no impurities. used for the prevention of a number of diseases in traditional medicines (19,20). Anthraquinones and stilbenes are the Cell culture. RAW264.7 cells were obtained from the primary constituents from the rhizomes of R. undulatum. American Type Culture Collection (Manassas, VA, USA) Anthraquinones have a laxative effect (21), whereas the and were cultured in Dulbecco's modified essential medium stilbenes from this plant exhibit various pharmacological with 10% heat-inactivated fetal bovine serum (FBS; Cambrex, activities, which include antioxidant, anti-inflammatory Charles City, IA, USA) and penicillin (100 U/ml)-streptomycin and hepatoprotective effects (22,23). Desoxyrhapontigenin (100 µg/ml). The cells were cultured at 37˚C in a humidified (DRG) is a stilbene compound isolated from the rhizomes 5% CO2 atmosphere. of R. undulatum and has an anti-inflammatory effect via activating the nuclear factor erythroid 2-related factor 2/heme Isolation of BMMs and osteoclast differentiation. Bone oxygenase-1 pathway and attenuating the NF-κB and MAPK marrow cells were isolated from the femurs and tibias of pathways in macrophages (24). However, the anti-osteoclasto- 6-week-old male ICR mice weighing 22-25 g (DBL, Emseong, genic effect of DRG and its underlying mechanisms remain to Chungbuk, Korea) housed at a temperature of 24±2˚C and be fully elucidated. On the basis of the association between humidity of 55±10% controlled colony room under a 12 h light chronic inflammatory and bone diseases (25), the present study and 12 h dark cycle. All mice were allowed ad libitum access aimed to determine the pharmacological effects of DRG on to a standard chow diet and water prior to all experiments. The RANKL-induced osteoclast formation and function in mouse bone marrow cells were then cultured in α-MEM (HyClone; bone marrow macrophages (BMMs) and on bone loss induced GE Healthcare Life Sciences, Logan, UT, USA) containing by lipopolysaccharide (LPS) in an in vivo animal model. It 10% FBS, 100 U/ml penicillin, 100 µg/ml streptomycin and was demonstrated that DRG suppressed RANKL-induced 10 ng/ml M‑CSF (Prospec-Tany TechnoGene Ltd., East osteoclast formation at an early stage of osteoclastogenesis in Brunswick, NJ, USA) overnight in a humidified incubator with BMMs and prevented LPS-induced bone destruction in the 5% CO2 at 37˚C. The floating cells were harvested and main- animal model. tained for 3 days with 30 ng/ml M‑CSF. The cells adhered to the culture dish were characterized as BMMs and used for Materials and methods subsequent experiments. The BMMs (5x104 cells/well) were cultured in 96-well plates and maintained with RANKL Isolation of stilbene derivatives. Dried R. undulatum L. (100 ng/ml) and M‑CSF (30 ng/ml) for 7 days in the presence rhizomes were purchased from the Yakryoung-si folk or absence of the indicated compounds. The medium was medicine market in Daegu, Korea, in May 2015. Botanical replaced every 2 days. The cells were then fixed for 15 min identification was performed by Professor Byung‑Sun Min in 3.7% formalin, permeabilized with 0.1% Triton X-100, (College of Pharmacy, Catholic University of Daegu, Hayang, and stained for TRAP with an acid phosphatase leukocyte Korea). A voucher specimen (CUD‑1188-1) was stored at the kit (Sigma-Aldrich; EMD Millipore, Billerica, MA, USA). College herbarium. The MeOH
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