{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T19:30:55Z","timestamp":1770060655207,"version":"3.49.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption and RANKL-induced signaling pathway using both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-\u03baB and Ca<jats:sup>2+<\/jats:sup>\/NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including <jats:italic>CtsK, Nfatc1, Trap, Ctr<\/jats:italic>. Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK\/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis.<\/jats:p>","DOI":"10.1038\/srep17605","type":"journal-article","created":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T10:22:21Z","timestamp":1448965341000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops"],"prefix":"10.1038","volume":"5","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiying","family":"Yue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huayun","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueyun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunbing","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiushan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,12,1]]},"reference":[{"key":"BFsrep17605_CR1","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/nrrheum.2010.133","volume":"6","author":"SA Krum","year":"2010","unstructured":"Krum, S. A., Chang, J., Miranda-Carboni, G. & Wang, C. Y. Novel functions for NFkappaB: inhibition of bone formation. Nat Rev Rheumatol 6, 607\u2013611 (2010).","journal-title":"Nat Rev Rheumatol"},{"key":"BFsrep17605_CR2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1124\/mol.109.057877","volume":"77","author":"JH Lee","year":"2010","unstructured":"Lee, J. H. et al. Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-kappaB signal. Mol Pharmacol 77, 17\u201325 (2010).","journal-title":"Mol Pharmacol"},{"key":"BFsrep17605_CR3","doi-asserted-by":"publisher","first-page":"7158","DOI":"10.1038\/srep07158.","volume":"4","author":"B Qi","year":"2014","unstructured":"Qi, B. et al. Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice. Sci Rep 4, 7158, 10.1038\/srep07158. (2014).","journal-title":"Sci Rep"},{"key":"BFsrep17605_CR4","doi-asserted-by":"publisher","first-page":"6218","DOI":"10.1038\/ncomms7218","volume":"6","author":"V Vives","year":"2015","unstructured":"Vives, V. et al. Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation. Nat Commun 6, 6218, 10.1038\/ncomms7218 (2015).","journal-title":"Nat Commun"},{"key":"BFsrep17605_CR5","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1056\/NEJMoa0809493","volume":"361","author":"SR Cummings","year":"2009","unstructured":"Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361, 756\u2013765 (2009).","journal-title":"N Engl J Med"},{"key":"BFsrep17605_CR6","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1002\/jbmr.1576","volume":"27","author":"X Wu","year":"2012","unstructured":"Wu, X. et al. Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-kappaB ligand-induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase\/activator protein 1 and Ca2+-nuclear factor of activated T-cells cytoplasmic 1 signaling pathways. J Bone Miner Res 27, 1298\u20131308 (2012).","journal-title":"J Bone Miner Res"},{"key":"BFsrep17605_CR7","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/jbmr.320","volume":"26","author":"LF Bonewald","year":"2011","unstructured":"Bonewald, L. F. The amazing osteocyte. J Bone Miner Res 26, 229\u2013238 (2011).","journal-title":"J Bone Miner Res"},{"key":"BFsrep17605_CR8","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.bone.2006.09.023","volume":"40","author":"M Asagiri","year":"2007","unstructured":"Asagiri, M. & Takayanagi, H. The molecular understanding of osteoclast differentiation. Bone 40, 251\u2013264 (2007).","journal-title":"Bone"},{"key":"BFsrep17605_CR9","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH645>3.0.CO;2-Q","volume":"192","author":"TJ Chambers","year":"2000","unstructured":"Chambers, T. J. Regulation of the differentiation and function of osteoclasts. J Pathol 192, 4\u201313 (2000).","journal-title":"J Pathol"},{"key":"BFsrep17605_CR10","doi-asserted-by":"publisher","first-page":"3540","DOI":"10.1073\/pnas.96.7.3540","volume":"96","author":"H Hsu","year":"1999","unstructured":"Hsu, H. et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96, 3540\u20133545 (1999).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep17605_CR11","doi-asserted-by":"publisher","first-page":"754","DOI":"10.3390\/molecules20010754","volume":"20","author":"M Liu","year":"2015","unstructured":"Liu, M. et al. Pharmacological profile of xanthohumol, a prenylated flavonoid from hops (Humulus lupulus). Molecules 20, 754\u2013779 (2015).","journal-title":"Molecules"},{"key":"BFsrep17605_CR12","doi-asserted-by":"publisher","first-page":"3914","DOI":"10.1172\/JCI69493","volume":"123","author":"S Takeshita","year":"2013","unstructured":"Takeshita, S. et al. Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J Clin Invest 123, 3914\u20133924 (2013).","journal-title":"J Clin Invest"},{"key":"BFsrep17605_CR13","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1021\/jm5016507","volume":"58","author":"B Zhang","year":"2015","unstructured":"Zhang, B. et al. Synthesis of xanthohumol analogues and discovery of potent thioredoxin reductase inhibitor as potential anticancer agent. J Med Chem 58, 1795\u20131805 (2015).","journal-title":"J Med Chem"},{"key":"BFsrep17605_CR14","doi-asserted-by":"publisher","first-page":"19000","DOI":"10.1074\/jbc.M112.445452","volume":"288","author":"JS Kirkwood","year":"2013","unstructured":"Kirkwood, J. S. et al. A metabolomics-driven elucidation of the anti-obesity mechanisms of xanthohumol. J Biol Chem 288, 19000\u201319013 (2013).","journal-title":"J Biol Chem"},{"key":"BFsrep17605_CR15","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.fct.2013.08.047","volume":"62","author":"KS Suh","year":"2013","unstructured":"Suh, K. S. et al. Xanthohumol modulates the expression of osteoclast-specific genes during osteoclastogenesis in RAW264.7 cells. Food Chem Toxicol 62, 99\u2013106 (2013).","journal-title":"Food Chem Toxicol"},{"key":"BFsrep17605_CR16","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.bbrc.2011.04.113","volume":"409","author":"HM Jeong","year":"2011","unstructured":"Jeong, H. M. et al. Xanthohumol from the hop plant stimulates osteoblast differentiation by RUNX2 activation. Biochem Biophys Res Commun 409, 82\u201389 (2011).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep17605_CR17","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1038\/nprot.2006.179","volume":"1","author":"V Vichai","year":"2006","unstructured":"Vichai, V. & Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1, 1112\u20131116 (2006).","journal-title":"Nat Protoc"},{"key":"BFsrep17605_CR18","doi-asserted-by":"publisher","first-page":"967","DOI":"10.2174\/156652412802480871","volume":"12","author":"Z Li","year":"2012","unstructured":"Li, Z. et al. Plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment. Current molecular medicine 12, 967\u2013981 (2012).","journal-title":"Current molecular medicine"},{"key":"BFsrep17605_CR19","doi-asserted-by":"publisher","first-page":"3122","DOI":"10.1021\/jm201540h","volume":"55","author":"J Xu","year":"2012","unstructured":"XuvJ. et al. Synthesis and biological evaluation of heterocyclic ring-fused betulinic acid derivatives as novel inhibitors of osteoclast differentiation and bone resorption. J Med Chem 55, 3122\u20133134 (2012).","journal-title":"J Med Chem"},{"key":"BFsrep17605_CR20","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1002\/jbmr.242","volume":"26","author":"C Li","year":"2011","unstructured":"Li, C. et al. Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-kappaB and MAPK signaling pathways. J Bone Miner Res 26, 644\u2013656 (2011).","journal-title":"J Bone Miner Res"},{"key":"BFsrep17605_CR21","doi-asserted-by":"publisher","first-page":"6206","DOI":"10.1158\/0008-5472.CAN-13-1049","volume":"73","author":"X Tang","year":"2013","unstructured":"Tang, X. et al. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Galphaq-p63RhoGEF-Rho GTPase pathway. Cancer Res 73, 6206\u20136218 (2013).","journal-title":"Cancer Res"},{"key":"BFsrep17605_CR22","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1093\/jnci\/djs485","volume":"105","author":"Y Fang","year":"2013","unstructured":"Fang, Y. et al. Inhibition of breast cancer metastases by a novel inhibitor of TGFbeta receptor 1. J Natl Cancer Inst 105, 47\u201358 (2013).","journal-title":"J Natl Cancer Inst"},{"key":"BFsrep17605_CR23","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.gene.2009.06.013","volume":"446","author":"W Balkan","year":"2009","unstructured":"Balkan, W. et al. Identification of NFAT binding sites that mediate stimulation of cathepsin K promoter activity by RANK ligand. Gene 446, 90\u201398 (2009).","journal-title":"Gene"},{"key":"BFsrep17605_CR24","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/S0006-291X(03)00695-8","volume":"305","author":"ZH Lee","year":"2003","unstructured":"Lee, Z. H. & Kim, H. H. Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun 305, 211\u2013214 (2003).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep17605_CR25","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s007740300021","volume":"21","author":"S Tanaka","year":"2003","unstructured":"Tanaka, S. et al. Signal transduction pathways regulating osteoclast differentiation and function. J Bone Miner Metab 21, 123\u2013133 (2003).","journal-title":"J Bone Miner Metab"},{"key":"BFsrep17605_CR26","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1172\/JCI200419657","volume":"114","author":"F Ikeda","year":"2004","unstructured":"Ikeda, F. et al. Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest 114, 475\u2013484 (2004).","journal-title":"J Clin Invest"},{"key":"BFsrep17605_CR27","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1126\/science.7939685","volume":"266","author":"AE Grigoriadis","year":"1994","unstructured":"Grigoriadis, A. E. et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266, 443\u2013448 (1994).","journal-title":"Science"},{"key":"BFsrep17605_CR28","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/nrg1122","volume":"4","author":"SL Teitelbaum","year":"2003","unstructured":"Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nat Rev Genet 4, 638\u2013649 (2003).","journal-title":"Nat Rev Genet"},{"key":"BFsrep17605_CR29","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1016\/j.intimp.2010.08.017","volume":"10","author":"HJ Kim","year":"2010","unstructured":"Kim, H. J. et al. Gymnasterkoreayne F inhibits osteoclast formation by suppressing NFATc1 and DC-STAMP expression. Int Immunopharmacol 10, 1440\u20131447 (2010).","journal-title":"Int Immunopharmacol"},{"key":"BFsrep17605_CR30","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1007\/s00109-004-0612-6","volume":"83","author":"H Takayanagi","year":"2005","unstructured":"Takayanagi, H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med (Berl) 83, 170\u2013179 (2005).","journal-title":"J Mol Med (Berl)"},{"key":"BFsrep17605_CR31","doi-asserted-by":"publisher","first-page":"2584","DOI":"10.1074\/jbc.M805280200","volume":"284","author":"SR Wilson","year":"2009","unstructured":"Wilson, S. R., Peters, C., Saftig, P. & Bromme, D. Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption. J Biol Chem 284, 2584\u20132592 (2009).","journal-title":"J Biol Chem"},{"key":"BFsrep17605_CR32","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1038\/nri2062","volume":"7","author":"H Takayanagi","year":"2007","unstructured":"Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7, 292\u2013304 (2007).","journal-title":"Nat Rev Immunol"},{"key":"BFsrep17605_CR33","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1196\/annals.1443.016","volume":"1143","author":"A Leibbrandt","year":"2008","unstructured":"Leibbrandt, A. & Penninger, J. M. RANK\/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 1143, 123\u2013150 (2008).","journal-title":"Ann N Y Acad Sci"},{"key":"BFsrep17605_CR34","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/ni.1706","volume":"10","author":"LB Ivashkiv","year":"2009","unstructured":"Ivashkiv, L. B. Cross-regulation of signaling by ITAM-associated receptors. Nat Immunol 10, 340\u2013347 (2009).","journal-title":"Nat Immunol"},{"key":"BFsrep17605_CR35","doi-asserted-by":"publisher","first-page":"34120","DOI":"10.1074\/jbc.273.51.34120","volume":"273","author":"L Galibert","year":"1998","unstructured":"Galibert, L. et al. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J Biol Chem 273, 34120\u201334127 (1998).","journal-title":"J Biol Chem"},{"key":"BFsrep17605_CR36","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1124\/mol.58.6.1536","volume":"58","author":"ZH Lee","year":"2000","unstructured":"Lee, Z. H. et al. Activation of c-Jun N-terminal kinase and activator protein 1 by receptor activator of nuclear factor kappaB. Mol Pharmacol 58, 1536\u20131545 (2000).","journal-title":"Mol Pharmacol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep17605","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17605.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17605.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T19:15:40Z","timestamp":1672946140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep17605"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,1]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,22]]}},"alternative-id":["BFsrep17605"],"URL":"https:\/\/doi.org\/10.1038\/srep17605","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,1]]},"assertion":[{"value":"23 June 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17605"}}