{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T13:18:22Z","timestamp":1780060702195,"version":"3.54.0"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1A2B5B02002516"],"award-info":[{"award-number":["2021R1A2B5B02002516"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2019R1C1C1011198"],"award-info":[{"award-number":["2019R1C1C1011198"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2019R1A5A6099645"],"award-info":[{"award-number":["2019R1A5A6099645"]}],"id":[{"id":"10.13039\/501100003725","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":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Many bone diseases such as osteoporosis and periodontitis are caused by hyperactivation of osteoclasts. Calcium (Ca<jats:sup>2+<\/jats:sup>) signals are crucial for osteoclast differentiation and function. Thus, the blockade of Ca<jats:sup>2+<\/jats:sup> signaling may be a strategy for regulating osteoclast activity and has clinical implications. Flunarizine (FN) is a Ca<jats:sup>2+<\/jats:sup> channel antagonist that has been used for reducing migraines. However, the role of FN in osteoclast differentiation and function remains unknown. Here, we investigated whether FN regulates osteoclastogenesis and elucidated the molecular mechanism. FN inhibited osteoclast differentiation along with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and attenuated osteoclast maturation and bone resorption. FN inhibition of osteoclast differentiation was restored by ectopic expression of constitutively active NFATc1. FN reduced calcium oscillations and its inhibition of osteoclast differentiation and resorption function was reversed by ionomycin, an ionophore that binds Ca<jats:sup>2+<\/jats:sup>. FN also inhibited Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase IV (CaMKIV) and calcineurin leading to a decrease in the cAMP\u2010responsive element\u2010binding protein\u2010dependent cFos and peroxisome proliferator\u2010activated receptor\u2010\u03b3 coactivator 1\u03b2 expression, and NFATc1 nuclear translocation. These results indicate that FN inhibits osteoclastogenesis via regulating CaMKIV and calcineurin as a Ca<jats:sup>2+<\/jats:sup> channel blocker. In addition, FN\u2010induced apoptosis in osteoclasts and promoted osteogenesis. Furthermore, FN protected lipopolysaccharide\u2010 and ovariectomy\u2010induced bone destruction in mouse models, suggesting that it has therapeutic potential for treating inflammatory bone diseases and postmenopausal osteoporosis.<\/jats:p>","DOI":"10.1002\/jcp.30496","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T08:53:55Z","timestamp":1625129635000},"page":"8239-8252","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis"],"prefix":"10.1002","volume":"236","author":[{"given":"Hyun Jin","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiae","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong\u2010Rak","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye In","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjeong","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Ha","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeong Ju","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3902-1058","authenticated-orcid":false,"given":"TaeSoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6042-0435","authenticated-orcid":false,"given":"Dong Min","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Oral Biology Yonsei University College of Dentistry Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1280-0067","authenticated-orcid":false,"given":"Woojin","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Life Science and the Research Center for Cellular Homeostasis Ewha Womans University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/36593"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2006.09.023"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.21553"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25389"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2020.53.3.147"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7939685"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01660"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1102703"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.07.030"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2010.11.002"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1910"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2019.52.11.013"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29968"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-2888-2_41"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21103646"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202525"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2020.53.4.220"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201900862R"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201800866RR"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708935200"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-020-0090-7"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.1981.hed2106235.x"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/35085068"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3000665"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpmo.21"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5484.1508"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2005.00331.x"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1515"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1646483"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2019.11.004"},{"issue":"1","key":"e_1_2_8_33_1","first-page":"169","article-title":"Calcium antagonist effects on low\u2010threshold (T\u2010type) calcium current in rat isolated hippocampal CA1 pyramidal neurons","volume":"256","author":"Takahashi K.","year":"1991","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2062"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5484.1504"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(91)90606-V"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00175798"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2005.11.007"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2005.00332.x"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00255"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.081239"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0162-3109(91)90003-H"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20675"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3398"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.238"}],"container-title":["Journal of Cellular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.30496","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcp.30496","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.30496","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T04:10:33Z","timestamp":1693195833000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcp.30496"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1002\/jcp.30496"],"URL":"https:\/\/doi.org\/10.1002\/jcp.30496","archive":["Portico"],"relation":{},"ISSN":["0021-9541","1097-4652"],"issn-type":[{"value":"0021-9541","type":"print"},{"value":"1097-4652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,30]]},"assertion":[{"value":"2021-01-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}