{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:10:32Z","timestamp":1792131032642,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100010618","name":"Guangzhou University of Chinese Medicine","doi-asserted-by":"publisher","award":["Visiting Program for Graduate Students 20172101024"],"award-info":[{"award-number":["Visiting Program for Graduate Students 20172101024"]}],"id":[{"id":"10.13039\/501100010618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1107828"],"award-info":[{"award-number":["APP1107828"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1127156"],"award-info":[{"award-number":["APP1127156"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1163933"],"award-info":[{"award-number":["APP1163933"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Excessive activity of osteoclasts contributes to skeletal diseases such as osteoporosis and osteolysis. However, current drugs targeting osteoclast have various deficiencies, placing natural compounds as substitutions of great potential. Roburic acid (RA) is a triterpenoid exacted from Radix Gentianae Macrophyllae, which exhibits inhibitory effects on inflammation and oxidation. By employing an in vitro osteoclastogenesis model, this study investigates the effects and mechanisms of RA on intracellular signaling induced by receptor activator of nuclear factor\u2010\u03baB ligand (RANKL). As expected, RA at a concentration scope from 1 to 10\u2009\u03bcM dampened the osteoclast differentiation of bone marrow macrophages (BMMs) but without cell toxicity. Interestingly, RA showed no effect on osteoblastogenesis in vitro. Furthermore, RA mitigated F\u2010actin ring formation, hydroxyapatite resorption, and gene expression in osteoclasts. Mechanistically, RA suppressed TNF receptor\u2010associated factor 6 (TRAF6), the crucial adaptor protein following RANKL\u2010RANK binding. On the one hand, RA downregulated the nuclear factor\u2010\u03baB (NF\u2010\u03baB) activity, extracellular regulated protein kinases (ERK) phosphorylation, and calcium oscillations. On the other hand, RA upregulated the antioxidative response element (ARE) response and the protein expression of heme oxygenase (HO)\u20101. These upstream alterations eventually led to the suppression of the nuclear factor of activated T cells 1 (NFATc1) activity and the expression of proteins involved in osteoclastogenesis and bone resorption. Furthermore, by using an ovariectomized (OVX) mice model, RA was found to have therapeutic effects against bone loss. On account of these findings, RA could be used to restrain osteoclasts for treating osteoporosis and other osteolytic diseases.<\/jats:p>","DOI":"10.1002\/jcp.30642","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T06:20:09Z","timestamp":1637302809000},"page":"1790-1803","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Roburic acid attenuates osteoclastogenesis and bone resorption by targeting RANKL\u2010induced intracellular signaling pathways"],"prefix":"10.1002","volume":"237","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3769-0784","authenticated-orcid":false,"given":"Gang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, First Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou China"},{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"},{"name":"Guangzhou University of Chinese Medicine Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"},{"name":"Department of Orthopaedics Erasmus University Medical Center Rotterdam Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbo","family":"He","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"},{"name":"Department of Orthopaedics, Second Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, First Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou China"},{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Guangdong Second Traditional Chinese Medicine Hospital Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbo","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Third Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Third Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2021-8309","authenticated-orcid":false,"given":"Jiake","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.12.1741"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202009200"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2009.06.013"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.567685"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2457"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2010.02.007"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH645>3.0.CO;2-Q"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.30206"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-017-0636-z"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2005.12.012"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2011.23"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.51.34120"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600564"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01344"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309193200"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2015.03.022"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.46.120604.141046"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2888"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2012.03.021"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-09-3662"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2019.06.3918"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.35414"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204386"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12882"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30045"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5484.1508"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21238965"},{"issue":"12","key":"e_1_2_8_29_1","first-page":"1410","article-title":"Regulation of osteoclast differentiation and function by the CaMK\u2010CREB pathway","volume":"12","author":"Sato K.","year":"2006","journal-title":"Nature Medicine (New York, NY, United States)"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.06.047"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2006.10.001"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3031"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/np500198g"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389450118666170321105425"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.081239"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103976"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2000.15.11.2178"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI4165"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2827"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2018.04.020"}],"container-title":["Journal of Cellular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.30642","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcp.30642","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.30642","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T09:36:52Z","timestamp":1692956212000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcp.30642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,19]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,3]]}},"alternative-id":["10.1002\/jcp.30642"],"URL":"https:\/\/doi.org\/10.1002\/jcp.30642","archive":["Portico"],"relation":{},"ISSN":["0021-9541","1097-4652"],"issn-type":[{"value":"0021-9541","type":"print"},{"value":"1097-4652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,19]]},"assertion":[{"value":"2021-07-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}