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Guggulsterone Inhibits Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor-KB Ligand and by Tumor Cells by Suppre

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Guggulsterone Inhibits Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor-KB Ligand and by Tumor Cells by Suppre Cancer Prevention Guggulsterone Inhibits Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor-KB Ligand and by Tumor Cells by Suppressing Nuclear Factor-KBActivation Haruyo Ichikawa and Bharat B. Aggarwal Abstract Bone resorption is commonly associated with aging and with certain types of cancer, including multiple myeloma and breast cancer.What induces bone resorption is not fully understood, but the role of osteoclasts is well established. Recently, receptor activator of nuclear factor-nB (NF-nB) ligand (RANKL), a member of the tumor necrosis factor superfamily, was implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling have the potential to inhibit bone resorption or osteoclastogenesis. Guggulsterone [4,17(20)- pregnadiene-3,16-dione], isolated from the guggul tree Commiphora mukul and used to treat osteoarthritis and bone fractures, was recently shown to antagonize the farnesoid X receptor, decrease the expression of bile acid ^ activated genes, and suppress the NF-nB activation induced by various carcinogens.We investigated whether guggulsterone could modulate RANKL signaling and osteoclastogenesis induced by RANKL or tumor cells.We found that treatment of monocytes with guggulsterone suppressed RANKL-activated NF-nB activation (as indicated by gel-shift assay) and that this suppression correlated with inhibition of InBa kinase and phosphorylation and degradation of InBa, an inhibitor of NF-nB. Guggulsterone also suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. Suppression of osteoclastogenesis by the NF-nB-specific inhibitory peptide implies a link between NF-nBand osteoclastogenesis. Finally, differentiation to osteoclasts induced by coincubating human breast tumor cells (MDA-MB-468) or human multiple myeloma (U266) cells with monocytes was also completely suppressed by guggulsterone. Collectively, our results indicate that guggulsterone suppresses RANKL and tumor cell ^ induced osteoclastogenesis by suppressing the activation of NF-nB. Osteoclasts are multinucleated cells belonging to the mono- ligand (5). RANKL, which is expressed on the surface of cyte macrophage lineage that form through the fusion of their osteoblastic/stromal cells, is directly involved in the differen- mononuclear precursors. This multistep differentiation process tiation of monocyte macrophages into osteoclasts (3, 5, 6). is under the control of the bone microenvironment, which Mice with disruptions in the RANKL gene show a lack of includes stromal cells, osteoblasts, and local factors (1). One of osteoclasts, severe osteopetrosis, and defective tooth eruption, the key factors mediating osteoclastogenesis is receptor indicating that RANKL is essential for osteoclast differentiation activator of nuclear factor-nB (NF-nB) ligand (RANKL; ref. 2), (7). RANKL-induced osteoclastogenesis is mediated through a member of the tumor necrosis factor (TNF) family that has the cell surface receptor RANK. The interaction of RANKL with also been called osteoclast differentiation factor (3), TNF- RANK leads to recruitment of TNF receptor–associated factor related activation–induced cytokine (4), and osteoprotegerin adapter proteins and activation of NF-nB signaling pathways (8–11). Selective modulation of RANKL signaling pathways may have important therapeutic implications for the treatment of bone diseases associated with enhanced bone resorption, Authors’ Affiliation: Cytokine Research Laboratory, Department of Experimental such as osteoporosis, osteoarthritis, and cancer-induced bone Therapeutics,The University ofTexas M.D. Anderson Cancer Center, Houston,Texas Received 8/10/05; revised 11/1/05; accepted 11/11/05. loss. Thus, agents that can suppress RANKL signaling may be Grant support: Clayton Foundation for Research, Department of Defense U.S. able to suppress osteoclastogenesis-induced bone loss. Army Breast Cancer Research Program grant BC010610, NIH grant P01CA91844 A phytochemical that has aroused considerable interest is on lung chemoprevention, and NIH P50 Head and Neck Specialized Programs of guggulsterone [4,17 (20)-pregnadiene-3,16-dione], a plant Research Excellence (B.B. Aggarwal). sterol derived from the gum resin (guggulu) of the tree The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance Commiphora mukul. The resin has been used in Ayurvedic with 18 U.S.C. Section 1734 solely to indicate this fact. medicine for centuries to treat a variety of ailments, including Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory, obesity, bone fractures, arthritis, inflammation, cardiovascular Department of Experimental Therapeutics, Box 143, The University of Texas M.D. disease, and lipid disorders (12, 13). The anti-arthritic and anti- Anderson Cancer Center, 1515 Holcombe Boulevard, Houston,TX 77030. Phone: 713-792-3503. ext. 6459; Fax: 713-794-1613; E-mail: [email protected]. inflammatory activity of gum guggul was shown as early as F 2006 American Association for Cancer Research. 1960 by Gujral et al. (14) followed by a report of activity in doi:10.1158/1078-0432.CCR-05-1749 experimental arthritis induced by mycobacterial adjuvant (15) Clin Cancer Res 2006;12(2) January 15, 2006 662 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2006 American Association for Cancer Research. Guggulsterone Suppresses Osteoclastogenesis and another on the effectiveness of guggul for treating oligonucleotide (15 Ag of protein with 16 fmol of DNA) from the HIV osteoarthritis of the knee (16). Recent studies have shown that long terminal repeat 5V-TTGTTACAAGGGACTTTCCGCTGGGGACTTTC- n guggulsterone is an antagonist for the bile acid receptor CAGGGAGGCGTGG-3V(boldface indicates NF- B binding sites) for 30 j farnesoid X receptor (17, 18). Other studies have shown that minutes at 37 C, and the DNA-protein complexes formed were separated from free oligonucleotide on 6.6 % native polyacrylamide guggulsterone enhances transcription of the bile salt export gels. A double-stranded mutated oligonucleotide, 5V-TTGTTACAACT- pump (19), thereby regulating cholesterol homeostasis. Our CACTTTCCGCTGCTCACTTTCCAGGGAGGCGTGG-3V,wasusedto laboratory reported that guggulsterone suppressed the DNA examine the specificity of binding of NF-nB to the DNA. The specificity binding of NF-nB induced by various carcinogens and of binding was also examined by competition with the unlabeled inflammatory agents (20). oligonucleotide. For supershift assays, nuclear extracts from TNF-treated Whether guggulsterone can suppress RANKL-induced NF-nB cells were incubated with antibodies against either p50 or p65 of NF-nB activation and osteoclastogenesis induced by RANKL and by for 15 minutes at 37jC before the complexes were analyzed by tumor cells was investigated. We show that guggulsterone electrophoretic mobility shift assays. The dried gels were visualized, suppressed the RANKL-induced NF-nB activation pathway by and radioactive bands were quantified by a Phosphorimager (Molecular inhibiting InBa kinase (IKK); moreover, this effect correlated Dynamics, Sunnyvale, CA) equipped with ImageQuant software. Western blotting analysis. To determine the levels of protein with the suppression of osteoclastogenesis induced by RANKL expression in the cytoplasm or nucleus, we prepared extracts (24) and or by breast cancer or multiple myeloma cells. fractionated them by SDS-PAGE. After electrophoresis, the proteins were electrotransferred to nitrocellulose membranes, blotted with each Materials and Methods antibody, and detected with enhanced chemiluminescence reagent (Amersham, Piscataway, NJ). The bands obtained were quantified by Materials. The rabbit polyclonal antibodies to InBa p50 and p65 using NIH Imaging software (Bethesda, MD). were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). IKK assay. To determine the effect of guggulsterone on TNF-induced Antibody against phospho-InBa was purchased from Cell Signaling IKK activation, we used a method described elsewhere (25). Briefly, the Technology (Beverly, MA). Anti-IKK-a and anti-IKK-h antibodies were IKK complex from whole-cell extracts (400 Ag) was precipitated with kindly provided by Imgenex (San Diego, CA). Goat anti-rabbit antibody against IKK-a followed by treatment with protein A/G- horseradish peroxidase conjugate was purchased from Bio-Rad Sepharose beads (Pierce). After 2 hours of incubation, the beads were (Hercules, CA); goat anti-mouse horseradish peroxidase and BioCoat washed with lysis buffer and assayed in a kinase assay mixture Osteologic Bone Cell Culture System were from BD Biosciences (San containing 50 mmol/L HEPES (pH 7.4), 20 mmol/L MgCl2, 2 mmol/L 32 Jose, CA); and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium DTT, 20 mCi [g- P]ATP, 10 mmol/L unlabeled ATP, and 2 Agof bromide was from Sigma-Aldrich (St. Louis, MO). Guggulsterone was substrate glutathione S-transferase (GST)/InBa (amino acids 1-54). After obtained from Steroid, Inc. (Newport, RI) and dissolved in DMSO as a incubation at 30jC for 30 minutes, the reaction was terminated by 100 mmol/L stock solution and stored at À20jC. DMEM/F12 medium, boiling with SDS sample buffer for 5 minutes. Finally, the protein was fetal bovine serum, 0.4% trypan blue vital stain, and an antibiotic- resolved on 10% SDS-PAGE, the gel was dried, and the radioactive bands antimycotic
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