{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T13:22:39Z","timestamp":1778937759962,"version":"3.51.4"},"reference-count":54,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002569","name":"Wonkwang University","doi-asserted-by":"publisher","award":["2024"],"award-info":[{"award-number":["2024"]}],"id":[{"id":"10.13039\/501100002569","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Excessive osteoclast activity in bone remodeling can lead to an imbalance between bone resorption and formation, a common occurrence in abnormal bone metabolic diseases. This research investigates the effect of Coptidis rhizoma water extract (CRW) on osteoclastogenesis provoked by RANKL in vitro and bone destruction mediated by ovariectomy (OVX) in vivo. CRW, prepared from dried Coptidis rhizoma (CR), was analyzed for its active compounds\u2014coptisine and berberine\u2014using HPLC analysis. CRW markedly decreased the size and number of TRAP-positive multinucleated cells (TRAP+ MNCs), suppressed F-actin ring formation, and diminished bone resorption in RANKL-treated cultures. In the early phase of differentiation, CRW suppressed the phosphorylation of MAPKs p38, JNK, and ERK, as well as NF-\u03baB p65, I\u03ba-B\u03b1, and Akt. CRW also down-regulated RANKL-mediated induction of c-Fos and NFATc1 and attenuated the activation of NFATc1- dependent genes, such as OSCAR, ATP6V0D2, ACP5 (TRAP), OC-STAMP, DC-STAMP, CTSK (cathepsin K), CALCR (calcitonin receptor), and MMP-9. In ovariectomized rats, micro-CT and histological analyses showed that CRW alleviated femoral bone destruction. These findings indicate that CRW restrains osteoclast differentiation and function and may have therapeutic potential for disorders driven by excessive osteoclast activity.<\/jats:p>","DOI":"10.3390\/ijms26178707","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Coptidis Rhizoma Water Extract Attenuates RANKL-Induced Osteoclast Differentiation via MAPK, Akt, and NF-\u03baB Pathways and Prevents Ovariectomy (OVX)-Mediated Bone Loss"],"prefix":"10.3390","volume":"26","author":[{"given":"Sang-Yong","family":"Han","sequence":"first","affiliation":[{"name":"Department of Herbal Medicine, College of Pharmacy, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Republic of Korea"},{"name":"Wonkwang Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6169-0402","authenticated-orcid":false,"given":"Yun-Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Herbal Medicine, College of Pharmacy, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Republic of Korea"},{"name":"Wonkwang Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, J.M., Lin, C., Stavre, Z., Greenblatt, M.B., and Shim, J.H. (2020). Osteoblast-Osteoclast Communication and Bone Homeostasis. Cells, 9.","DOI":"10.3390\/cells9092073"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"474","DOI":"10.2174\/1574888X14666190214163815","article-title":"Macrophages in Bone Homeostasis","volume":"14","author":"Kong","year":"2019","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Nedeva, I.R., Vitale, M., Elson, A., Hoyland, J.A., and Bella, J. (2021). Role of OSCAR Signaling in Osteoclastogenesis and Bone Disease. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.641162"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-pathmechdis-031521-040919","article-title":"Osteoclasts, Master Sculptors of Bone","volume":"18","author":"Veis","year":"2023","journal-title":"Annu. Rev. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"579","DOI":"10.2174\/1574888X14666191107103755","article-title":"Phospholipase C\u03b3 Signaling in Bone Marrow Stem Cell and Relevant Natural Compounds Therapy","volume":"15","author":"Liu","year":"2020","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","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 Miner. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Qu, Z., Zhang, B., Kong, L., Gong, Y., Feng, M., Gao, X., Wang, D., and Yan, L. (2022). Receptor activator of nuclear factor-\u03baB ligand-mediated osteoclastogenesis signaling pathway and related therapeutic natural compounds. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1043975"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.4248\/BR201301003","article-title":"Osteoclasts: New Insights","volume":"1","author":"Feng","year":"2013","journal-title":"Bone Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kitaura, H., Marahleh, A., Ohori, F., Noguchi, T., Shen, W.R., Qi, J., Nara, Y., Pramusita, A., Kinjo, R., and Mizoguchi, I. (2020). Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145169"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1084\/jem.20051150","article-title":"Autoamplification of NFATc1 expression determines its essential role in bone homeostasis","volume":"202","author":"Asagiri","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1172\/JCI45913","article-title":"OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice","volume":"121","author":"Barrow","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1210\/me.2007-0237","article-title":"NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP)","volume":"22","author":"Kim","year":"2008","journal-title":"Mol. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1080\/13880209.2019.1577466","article-title":"Coptidis Rhizoma: A comprehensive review of its traditional uses, botany, phytochemistry, pharmacology and toxicology","volume":"57","author":"Wang","year":"2019","journal-title":"Pharm. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.3109\/13880209.2014.952838","article-title":"Antidiabetic mechanism of Coptis chinensis polysaccharide through its antioxidant property involving the JNK pathway","volume":"53","author":"Jiang","year":"2015","journal-title":"Pharm. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.neulet.2011.05.017","article-title":"Neuroprotective effect of Jatrorrhizine on hydrogen peroxide-induced cell injury and its potential mechanisms in PC12 cells","volume":"498","author":"Luo","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jep.2015.10.028","article-title":"Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives","volume":"176","author":"Wang","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.3892\/mmr.2017.7119","article-title":"Metabolic characteristics of Rhizoma Coptidis intervention in spontaneously hypertensive rats: Insights gained from metabolomics analysis of serum","volume":"16","author":"Yang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1211\/0022357023024","article-title":"Coptidis Rhizoma: Protective effects against peroxynitrite-induced oxidative damage and elucidation of its active components","volume":"56","author":"Yokozawa","year":"2004","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13020-018-0171-3","article-title":"Coptidis rhizoma and its main bioactive components: Recent advances in chemical investigation, quality evaluation and pharmacological activity","volume":"13","author":"Meng","year":"2018","journal-title":"Chin. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1142\/S0192415X19500228","article-title":"Berberine Suppresses RANKL-Induced Osteoclast Differentiation by Inhibiting c-Fos and NFATc1 Expression","volume":"47","author":"Han","year":"2019","journal-title":"Am. J. Chin. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11418-011-0537-7","article-title":"Coptisine inhibits RANKL-induced NF-\u03baB phosphorylation in osteoclast precursors and suppresses function through the regulation of RANKL and OPG gene expression in osteoblastic cells","volume":"66","author":"Lee","year":"2012","journal-title":"J. Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Smith, J.K. (2020). Osteoclasts and Microgravity. Life, 10.","DOI":"10.20944\/preprints202007.0714.v1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11154-006-9009-x","article-title":"Molecular regulation of osteoclast activity","volume":"7","author":"Bruzzaniti","year":"2006","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kim, E.J., Lee, H., Kim, M.H., and Yang, W.M. (2018). Inhibition of RANKL-stimulated osteoclast differentiation by Schisandra chinensis through down-regulation of NFATc1 and c-fos expression. BMC Complement. Altern. Med., 18.","DOI":"10.1186\/s12906-018-2331-5"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.jep.2014.01.011","article-title":"Subchronic toxicity study of Coptidis rhizoma in rats","volume":"152","author":"Lee","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1078\/094471103321648610","article-title":"The effects of Coptidis Rhizoma extract on a hypercholesterolemic animal model","volume":"10","author":"Yokozawa","year":"2003","journal-title":"Phytomedicine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.freeradbiomed.2022.12.102","article-title":"17\u03b2-estradiol plays the anti-osteoporosis role via a novel ESR1-Keap1-Nrf2 axis-mediated stress response activation and Tmem119 upregulation","volume":"195","author":"Yang","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lee, G.H., Hoang, T.H., Lee, H.Y., Lim, Y.J., Kim, J.H., Jung, S.J., Chae, S.W., Rashid, M.M.U., Chae, H.J., and Yoon, S.J. (2023). Ramie leaf Extract Alleviates Bone Loss in Ovariectomized Rats-The Involvement of ROS and Its Associated Signalings. Nutrients, 15.","DOI":"10.3390\/nu15030745"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111836","DOI":"10.1016\/j.exger.2022.111836","article-title":"Ferroptosis\u2014A new target of osteoporosis","volume":"165","author":"Gao","year":"2022","journal-title":"Exp. Gerontol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108168","DOI":"10.1016\/j.pharmthera.2022.108168","article-title":"Advances in pathogenesis and therapeutic strategies for osteoporosis","volume":"237","author":"Song","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.2174\/0929867327666200330142432","article-title":"Osteoporosis: Mechanism, Molecular Target and Current Status on Drug Development","volume":"28","author":"Li","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_33","first-page":"307","article-title":"Pharmacological agents and natural compounds: Available treatments for osteoporosis","volume":"71","author":"Martiniakova","year":"2020","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ekor, M. (2014). The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front. Pharmacol., 4.","DOI":"10.3389\/fphar.2013.00177"},{"key":"ref_35","unstructured":"Khan, M.S.A., and Ahmad, I. (2019). Herbal Medicine: Current Trends and Future Prospects. New Look to Phytomedicine, Academic Press."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9569","DOI":"10.18632\/aging.205885","article-title":"Attenuating bone loss in osteoporosis: The potential of corylin (CL) as a therapeutic agent","volume":"16","author":"Zhou","year":"2024","journal-title":"Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10732","DOI":"10.18632\/aging.205111","article-title":"Micheliolide prevents estrogen deficiency-induced bone loss via inhibiting osteoclast bone resorption","volume":"15","author":"Gan","year":"2023","journal-title":"Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10213","DOI":"10.18632\/aging.205068","article-title":"Icaritin ameliorates RANKL-mediated osteoclastogenesis and ovariectomy-induced osteoporosis","volume":"15","author":"Huang","year":"2023","journal-title":"Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"233","DOI":"10.11005\/jbm.2014.21.4.233","article-title":"Regulation of NFATc1 in Osteoclast Differentiation","volume":"21","author":"Kim","year":"2014","journal-title":"J. Bone Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1177\/002215540004800207","article-title":"Osteoclastic tartrate-resistant acid phosphatase (Acp 5): Its localization to dendritic cells and diverse murine tissues","volume":"48","author":"Hayman","year":"2000","journal-title":"J. Histochem. Cytochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jcb.10503","article-title":"Phosphatidylinositol 3-kinase coordinately activates the MEK\/ERK and AKT\/NFkappaB pathways to maintain osteoclast survival","volume":"89","author":"Gingery","year":"2003","journal-title":"J. Cell. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lee, K., Seo, I., Choi, M.H., and Jeong, D. (2018). Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103004"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1254\/jphs.11212FP","article-title":"The coffee diterpene kahweol prevents osteoclastogenesis via impairment of NFATc1 expression and blocking of Erk phosphorylation","volume":"118","author":"Fumimoto","year":"2012","journal-title":"J. Pharmacol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/j.0105-2896.2005.00332.x","article-title":"Fos\/AP-1 proteins in bone and the immune system","volume":"208","author":"Wagner","year":"2005","journal-title":"Immunol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/nm1197-1285","article-title":"Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2","volume":"3","author":"Iotsova","year":"1997","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Jimi, E., and Katagiri, T. (2022). Critical Roles of NF-\u03baB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147995"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27087","DOI":"10.3390\/ijms161125998","article-title":"Berberine Sulfate Attenuates Osteoclast Differentiation through RANKL Induced NF-\u03baB and NFAT Pathways","volume":"16","author":"Zhou","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ejphar.2007.11.013","article-title":"Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways","volume":"580","author":"Hu","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s41232-019-0111-3","article-title":"RANKL biology: Bone metabolism, the immune system, and beyond","volume":"40","author":"Ono","year":"2020","journal-title":"Inflamm. Regen."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.bone.2016.11.005","article-title":"ATF3 modulates calcium signaling in osteoclast differentiation and activity by associating with c-Fos and NFATc1 proteins","volume":"95","author":"Jeong","year":"2017","journal-title":"Bone"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1359\/jbmr.080325","article-title":"Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK","volume":"23","author":"Lee","year":"2008","journal-title":"J. Bone Miner. Res."},{"key":"ref_52","first-page":"89","article-title":"Ovariectomized rat model of osteoporosis: A practical guide","volume":"19","author":"Yousefzadeh","year":"2020","journal-title":"EXCLI J."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Han, S.Y., Kim, J.H., Jo, E.H., and Kim, Y.K. (2021). Eleutherococcus sessiliflorus Inhibits Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-Induced Osteoclast Differentiation and Prevents Ovariectomy (OVX)-Induced Bone Loss. Molecules, 26.","DOI":"10.3390\/molecules26071886"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8707\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:41:20Z","timestamp":1760035280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8707"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,6]]},"references-count":54,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178707"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178707","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,6]]}}}