{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:44:59Z","timestamp":1780638299820,"version":"3.54.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T00:00:00Z","timestamp":1699401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Osteoporosis, a prevalent osteolytic condition worldwide, necessitates effective strategies to inhibit excessive bone resorption by curbing osteoclast hyperactivation. Liquiritin (LIQ), an flavanone derivative employed in acute lung injury and rheumatoid arthritis treatment, possesses an unclear role in addressing excessive bone resorption. In this investigation, we found that LIQ demonstrates the ability to inhibit osteoclast formation and the bone-resorbing activity induced by RANKL. At a specific concentration, LIQ significantly attenuated NF-\u03baB-Luc activity induced by RANKL and curtailed NF-\u03baB activation in RANKL-stimulated RAW264.7 cells, resulting in reduced I\u03baB-\u03b1 breakdown and diminished nuclear NF-\u03baB levels. Furthermore, LIQ markedly inhibited RANKL-induced NFATc1 activation, as evidenced by diminished NFATc1 luciferase activity, reduced NFATc1 mRNA levels, and decreased nuclear NFATc1 protein levels. Subsequent experiments demonstrated that LIQ effectively restrained the RANKL-induced elevation of intracellular calcium as well as reactive oxygen species. Additionally, LIQ exhibited a downregulating effect on the expression of osteoclast-specific genes, which include <jats:italic>Acp5<\/jats:italic>, <jats:italic>Cathepsin K<\/jats:italic>, <jats:italic>Atp6v0d2<\/jats:italic>, <jats:italic>Nfatc1<\/jats:italic>, <jats:italic>c-Fos<\/jats:italic>, and <jats:italic>Mmp9<\/jats:italic>. Notably, our findings revealed the potential of LIQ to counteract decreased bone density in mice that underwent ovariectomy. Collectively, the data indicate that LIQ impedes osteoclast formation triggered by RANKL and the subsequent reduction in bone mass by mitigating ROS levels and suppressing the Ca<jats:sup>2+<\/jats:sup>\/MAPK-NFATc1 signaling pathway, suggesting its promising candidacy as a therapeutic agent for RANKL-mediated osteoporosis.<\/jats:p>","DOI":"10.3389\/fphar.2023.1287827","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T15:53:34Z","timestamp":1699545214000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["A novel Glycyrrhiza glabra extract liquiritin targeting NFATc1 activity and ROS levels to counteract ovariectomy-induced osteoporosis and bone loss in murine model"],"prefix":"10.3389","volume":"14","author":[{"given":"Guoju","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanqiang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenqiu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiushi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3576","DOI":"10.3390\/ijms20143576","article-title":"Reactive oxygen species in osteoclast differentiation and possible pharmaceutical targets of ROS-mediated osteoclast diseases","volume":"20","author":"Agidigbi","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3775","DOI":"10.1172\/JCI35711","article-title":"NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism","volume":"118","author":"Aliprantis","year":"2008","journal-title":"J. Clin. Invest."},{"key":"B3","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3389\/fphar.2014.00196","article-title":"Glutathione: new roles in redox signaling for an old antioxidant","volume":"5","author":"Aquilano","year":"2014","journal-title":"Front. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.bone.2006.09.023","article-title":"The molecular understanding of osteoclast differentiation","volume":"40","author":"Asagiri","year":"2007","journal-title":"Bone"},{"key":"B5","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1097\/GME.0000000000001831","article-title":"Management of osteoporosis in postmenopausal women: the 2021 position statement of the North American Menopause Society","volume":"28","year":"2021","journal-title":"Menopause N. Y. N."},{"key":"B6","doi-asserted-by":"publisher","first-page":"35","DOI":"10.3803\/EnM.2015.30.1.35","article-title":"NF-\u03baB-Mediated regulation of osteoclastogenesis","volume":"30","author":"Boyce","year":"2015","journal-title":"Endocrinol. Metab."},{"key":"B7","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/32419","article-title":"Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum","volume":"392","author":"de la Pompa","year":"1998","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2625","DOI":"10.1007\/s40520-022-02272-z","article-title":"Novel formulations of oral bisphosphonates in the treatment of osteoporosis","volume":"34","author":"Fuggle","year":"2022","journal-title":"Aging Clin. Exp. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"58","DOI":"10.5582\/bst.2021.01357","article-title":"Effects and mechanisms of microenvironmental acidosis on osteoclast biology","volume":"16","author":"Gong","year":"2022","journal-title":"Biosci. Trends"},{"key":"B10","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1097\/FJC.0000000000000788","article-title":"Role of NFATc1 in the bone-vascular Axis calcification paradox","volume":"75","author":"Gu","year":"2020","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B11","first-page":"347","article-title":"Biological basis of bone strength: anatomy, physiology and measurement","volume":"20","author":"Hart","year":"2020","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e392","DOI":"10.1002\/ctm2.392","article-title":"A novel RANKL-targeted flavonoid glycoside prevents osteoporosis through inhibiting NFATc1 and reactive oxygen species","volume":"11","author":"Hong","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.3390\/cells8121636","article-title":"The role of NF-\u03baB in physiological bone development and inflammatory bone diseases: is NF-\u03baB inhibition \u201ckilling two birds with one stone\u201d","volume":"8","author":"Jimi","year":"2019","journal-title":"Cells"},{"key":"B14","doi-asserted-by":"publisher","first-page":"3646","DOI":"10.3390\/ijms21103646","article-title":"The role of Ca2+-NFATc1 signaling and its modulation on osteoclastogenesis","volume":"21","author":"Kang","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.redox.2016.01.006","article-title":"Molecular regulatory mechanisms of osteoclastogenesis through cytoprotective enzymes","volume":"8","author":"Kanzaki","year":"2016","journal-title":"Redox Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e12740","DOI":"10.1111\/ecc.12740","article-title":"The biology of normal bone remodelling","volume":"26","author":"Katsimbri","year":"2017","journal-title":"Eur. J. Cancer Care (Engl.)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s12325-021-01936-y","article-title":"Denosumab in the treatment of osteoporosis: 10 Years later: a narrative review","volume":"39","author":"Kendler","year":"2022","journal-title":"Adv. Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"E2073","DOI":"10.3390\/cells9092073","article-title":"Osteoblast-osteoclast communication and bone homeostasis","volume":"9","author":"Kim","year":"2020","journal-title":"Cells"},{"key":"B19","doi-asserted-by":"publisher","first-page":"E5685","DOI":"10.3390\/ijms21165685","article-title":"Osteoclast multinucleation: review of current literature","volume":"21","author":"Kodama","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1827","DOI":"10.1089\/ars.2013.5341","article-title":"Role of heme oxygenase-1 in postnatal differentiation of stem cells: a possible cross-talk with microRNAs","volume":"20","author":"Kozakowska","year":"2014","journal-title":"Antioxid. Redox Signal"},{"key":"B21","doi-asserted-by":"publisher","first-page":"115471","DOI":"10.1016\/j.bone.2020.115471","article-title":"Epigenetic and transcriptional regulation of osteoclast differentiation","volume":"138","author":"Kurotaki","year":"2020","journal-title":"Bone"},{"key":"B22","doi-asserted-by":"publisher","first-page":"671783","DOI":"10.3389\/fphar.2021.671783","article-title":"The protective effect of liquiritin in hypoxia\/reoxygenation-induced disruption on blood brain barrier","volume":"12","author":"Li","year":"","journal-title":"Front. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1186\/s40001-021-00610-x","article-title":"A meta-analysis of the therapeutic effect of intranasal salmon calcitonin on osteoporosis","volume":"26","author":"Li","year":"","journal-title":"Eur. J. Med. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s43450-022-00233-1","article-title":"Liquiritin relieves oxygen-glucose reperfusion-induced neuronal injury via inhibition of the p38MAPK\/NF-\u03baB signaling pathway","volume":"32","author":"Liao","year":"2022","journal-title":"Rev. Bras. Farmacogn."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2271","DOI":"10.3390\/cells10092271","article-title":"Inhibition of cellular and animal inflammatory disease models by NF-\u03baB inhibitor DHMEQ","volume":"10","author":"Ma","year":"2021","journal-title":"Cells"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2937","DOI":"10.1002\/jcp.26042","article-title":"The roles of signaling pathways in bone repair and regeneration","volume":"233","author":"Majidinia","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.26402\/jpp.2020.3.01","article-title":"Pharmacological agents and natural compounds: available treatments for osteoporosis","volume":"71","author":"Martiniakova","year":"2020","journal-title":"J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc."},{"key":"B28","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/cr.2010.178","article-title":"Crosstalk of reactive oxygen species and NF-\u03baB signaling","volume":"21","author":"Morgan","year":"2011","journal-title":"Cell Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1097\/GRF.0000000000000572","article-title":"Bone health and osteoporosis prevention and treatment","volume":"63","author":"Mu\u00f1oz","year":"2020","journal-title":"Clin. Obstet. Gynecol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"195","DOI":"10.3389\/fimmu.2020.00195","article-title":"The role of calcium\u2013calcineurin\u2013NFAT signaling pathway in health and autoimmune diseases","volume":"11","author":"Park","year":"2020","journal-title":"Front. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"115257","DOI":"10.1016\/j.jep.2022.115257","article-title":"Pharmacological activities and pharmacokinetics of liquiritin: a review","volume":"293","author":"Qin","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1016\/S0140-6736(21)02646-5","article-title":"Drug therapy for osteoporosis in older adults","volume":"399","author":"Reid","year":"2022","journal-title":"Lancet lond. Engl."},{"key":"B33","doi-asserted-by":"publisher","first-page":"7571132","DOI":"10.1155\/2021\/7571132","article-title":"Glycyrrhiza genus: enlightening phytochemical components for pharmacological and health-promoting abilities","volume":"2021","author":"Sharifi-Rad","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/cr.2010.177","article-title":"Non-canonical NF-\u03baB signaling pathway","volume":"21","author":"Sun","year":"2011","journal-title":"Cell Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s00774-020-01191-1","article-title":"RANKL as the master regulator of osteoclast differentiation","volume":"39","author":"Takayanagi","year":"2021","journal-title":"J. Bone Min. Metab."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1093\/abbs\/gmaa098","article-title":"ROS signaling cascades: dual regulations for osteoclast and osteoblast","volume":"52","author":"Tao","year":"2020","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"B37","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00774-020-01162-6","article-title":"Osteoclast differentiation by RANKL and OPG signaling pathways","volume":"39","author":"Udagawa","year":"2021","journal-title":"J. Bone Min. Metab."},{"key":"B38","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.cytogfr.2008.11.007","article-title":"NF-kappaB modulators in osteolytic bone diseases","volume":"20","author":"Xu","year":"2009","journal-title":"Cytokine Growth Factor Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1080\/1061186X.2021.2013488","article-title":"Effects and mechanisms of natural plant active compounds for the treatment of osteoclast-mediated bone destructive diseases","volume":"30","author":"Xu","year":"2022","journal-title":"J. Drug Target."},{"key":"B40","doi-asserted-by":"publisher","first-page":"20030","DOI":"10.1074\/jbc.M116.731216","article-title":"NADPH oxidases are essential for macrophage differentiation","volume":"291","author":"Xu","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"132","DOI":"10.3390\/cells11010132","article-title":"Regulation of TNF-induced osteoclast differentiation","volume":"11","author":"Yao","year":"2021","journal-title":"Cells"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s00774-020-01175-1","article-title":"Discovery of the RANKL\/RANK\/OPG system","volume":"39","author":"Yasuda","year":"2021","journal-title":"J. Bone Min. Metab."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijsu.2019.03.004","article-title":"Teriparatide versus bisphosphonates for treatment of postmenopausal osteoporosis: a meta-analysis","volume":"66","author":"Yuan","year":"2019","journal-title":"Int. J. Surg. Lond. Engl."},{"key":"B44","doi-asserted-by":"publisher","first-page":"898634","DOI":"10.3389\/fendo.2022.898634","article-title":"Autophagy in bone remodeling: a regulator of oxidative stress","volume":"13","author":"Zhu","year":"2022","journal-title":"Front. Endocrinol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1287827\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T15:53:40Z","timestamp":1699545220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1287827\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,8]]},"references-count":44,"alternative-id":["10.3389\/fphar.2023.1287827"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1287827","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,8]]},"article-number":"1287827"}}