{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T22:00:42Z","timestamp":1785276042763,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T00:00:00Z","timestamp":1553212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biomedical Research Institute, Pusan National University Hospital","award":["2016-00"],"award-info":[{"award-number":["2016-00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bisphosphonates are one of the most widely used synthetic pyrophosphate analogues for the treatment of bone resorbing diseases such as osteoporosis, multiple myeloma, and bone metastases. Although the therapeutic usefulness of bisphosphonates mainly depends on their anti-osteoclastogenic effect, a severe side-effect of bisphosphonates called bisphosphonate-related osteonecrosis of the jaw (BRONJ) could not be explained by the anti-osteoclastogenic effect of bisphosphonates. In the present study, we have evaluated the changes in osteoclastogenesis- or osteoblastogenesis-supporting activities of osteocytes induced by bisphosphonates. Zoledronate, a nitrogen-containing bisphosphonate, markedly increased both the receptor activator of nuclear factor kB ligand (RANKL) as well as sclerostin in osteocyte-like MLO-Y4 cells, which were functionally revalidated by osteoclast\/osteoblast generating activities of the conditioned medium obtained from zoledronate-treated MLO-Y4 cells. Of note, the zoledronate treatment-induced upregulation of the RANKL expression was mediated by autocrine interleukin-6 (IL-6) and subsequent activation of the signal transducer and activator of transcription 3 (STAT3) pathway. These results were evidenced by the blunted RANKL expression in the presence of a Janus activated kinase (JAK2)\/STAT3 inhibitor, AG490. Also, the osteoclastogenesis-supporting activity was significantly decreased in zoledronate-treated MLO-Y4 cells in the presence of IL-6 neutralizing IgG compared to that of the control IgG. Thus, our results show previously unanticipated effects of anti-bone resorptive bisphosphonate and suggest a potential clinical importance of osteocytes in BRONJ development.<\/jats:p>","DOI":"10.3390\/ijms20061467","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T06:56:52Z","timestamp":1553497012000},"page":"1467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6\/RANKL Axis"],"prefix":"10.3390","volume":"20","author":[{"given":"Hyung Joon","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YunJeong","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon-Kyoung","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae Seok","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan 50612, Korea"},{"name":"Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Hun","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan 50612, Korea"},{"name":"Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Yeol","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan 50612, Korea"},{"name":"Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/0221-8747(81)90044-8","article-title":"Diphosphonates: History and mechanisms of action","volume":"3","author":"Fleisch","year":"1981","journal-title":"Metab. Bone Dis. Relat. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1248\/bpb.b16-01020","article-title":"Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)","volume":"40","author":"Endo","year":"2017","journal-title":"Biol. Pharm. Bull."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1126\/science.289.5484.1508","article-title":"Therapeutic approaches to bone diseases","volume":"289","author":"Rodan","year":"2000","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.2174\/1381612033453640","article-title":"New insights into the molecular mechanisms of action of bisphosphonates","volume":"9","author":"Rogers","year":"2003","journal-title":"Curr. Pharm. Des."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.bone.2011.04.022","article-title":"Bisphosphonates: The first 40 years","volume":"49","author":"Russell","year":"2011","journal-title":"Bone"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1177\/154405910708601102","article-title":"Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates","volume":"86","author":"Kimmel","year":"2007","journal-title":"J. Dent. Res."},{"key":"ref_7","first-page":"711","article-title":"Nitrogen-containing bisphosphonate mechanism of action","volume":"4","author":"Reszka","year":"2004","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1002\/1529-0131(200109)44:9<2201::AID-ART374>3.0.CO;2-E","article-title":"The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: Evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis","volume":"44","author":"Frith","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1124\/mol.61.5.1255","article-title":"Further insight into mechanism of action of clodronate: Inhibition of mitochondrial ADP\/ATP translocase by a nonhydrolyzable, adenine-containing metabolite","volume":"61","author":"Lehenkari","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/S0278-2391(03)00720-1","article-title":"Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic","volume":"61","author":"Marx","year":"2003","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1601-0825.2009.01568.x","article-title":"Bisphosphonate-related osteonecrosis: Genetic and acquired risk factors","volume":"15","author":"Sarasquete","year":"2009","journal-title":"Oral Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1177\/0300060518788987","article-title":"Pathogenesis of medication-related osteonecrosis of the jaw: A comparative study of in vivo and in vitro trials","volume":"46","author":"Holtmann","year":"2018","journal-title":"J. Int. Med. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.jcms.2017.05.028","article-title":"What is the effect of anti-resorptive drugs (ARDs) on the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A systematic review","volume":"45","author":"Aljohani","year":"2017","journal-title":"J. Craniomaxillofac. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1159\/000351194","article-title":"Zoledronic acid inhibits human osteoblast activities","volume":"59","author":"Basso","year":"2013","journal-title":"Gerontology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1177\/0022034511402995","article-title":"Bisphosphonates induce senescence in normal human oral keratinocytes","volume":"90","author":"Kim","year":"2011","journal-title":"J. Dent. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.coph.2016.02.003","article-title":"Osteocytes: The master cells in bone remodelling","volume":"28","author":"Prideaux","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00223-013-9774-y","article-title":"Osteocyte-driven bone remodeling","volume":"94","author":"Bellido","year":"2014","journal-title":"Calcif. Tissue Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ye, T., Cao, P., Qi, J., Zhou, Q., Rao, DS., and Qiu, S. (2017). Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186012"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.17219\/acem\/68739","article-title":"Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders","volume":"26","author":"Pietrzyk","year":"2017","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","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":"ref_21","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.molmed.2014.06.001","article-title":"Osteoclasts: More than \u2018bone eaters\u2019","volume":"20","author":"Charles","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"63S","DOI":"10.1016\/8756-3282(95)00180-L","article-title":"Role of cytokines in bone resorption","volume":"17","author":"Manolagas","year":"1995","journal-title":"Bone"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1159\/000465455","article-title":"IL-6 Enhances Osteocyte-Mediated Osteoclastogenesis by Promoting JAK2 and RANKL Activity In Vitro","volume":"41","author":"Wu","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.bone.2012.08.121","article-title":"Osteocyte control of osteoclastogenesis","volume":"54","author":"Nakashima","year":"2013","journal-title":"Bone"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1007\/s00228-012-1216-7","article-title":"Bisphosphonates: Effects on osteoblast","volume":"68","author":"Maruotti","year":"2012","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bone.2010.08.008","article-title":"Novel actions of bisphosphonates in bone: Preservation of osteoblast and osteocyte viability","volume":"49","author":"Bellido","year":"2011","journal-title":"Bone"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.bone.2003.08.013","article-title":"The nitrogen-containing bisphosphonate, zoledronic acid, increases mineralisation of human bone-derived cells in vitro","volume":"34","author":"Pan","year":"2004","journal-title":"Bone"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1007\/s11999-008-0409-y","article-title":"Alendronate enhances osteogenic differentiation of bone marrow stromal cells: A preliminary study","volume":"467","author":"Kim","year":"2009","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8674","DOI":"10.1016\/j.biomaterials.2010.07.096","article-title":"The effect of the local delivery of alendronate on human adipose-derived stem cell-based bone regeneration","volume":"31","author":"Wang","year":"2010","journal-title":"Biomaterials"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1742-7843.2005.pto_176.x","article-title":"In vitro comparison of clodronate, pamidronate and zoledronic acid effects on rat osteoclasts and human stem cell-derived osteoblasts","volume":"97","author":"Kellinsalmi","year":"2005","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1359\/jbmr.2002.17.11.2068","article-title":"MLO-Y4 osteocyte-like cells support osteoclast formation and activation","volume":"17","author":"Zhao","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/nm.2448","article-title":"Matrix-embedded cells control osteoclast formation","volume":"11","author":"Xiong","year":"2011","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/nm.2452","article-title":"Evidence for osteocyte regulation of bone homeostasis through RANKL expression","volume":"17","author":"Nakashima","year":"2011","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19301","DOI":"10.1074\/jbc.274.27.19301","article-title":"STAT3 activation in stromal\/osteoblastic cells is required for induction of the receptor activator of NF-kappaB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone","volume":"274","author":"Gubrij","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0070-2153(06)76004-5","article-title":"Wnt signaling: A key regulator of bone mass","volume":"76","author":"Baron","year":"2006","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1359\/jbmr.080216","article-title":"Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength","volume":"23","author":"Li","year":"2008","journal-title":"J. Bone Miner. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Wijenayaka, A.R., Kogawa, M., Lim, H.P., Bonewald, L.F., Findlay, D.M., and Atkins, G.J. (2011). Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025900"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1083\/jcb.201204067","article-title":"Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival","volume":"199","author":"Kim","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1136\/bmj.323.7309.391","article-title":"Mann-Whitney test is not just a test of medians: Differences in spread can be important","volume":"323","author":"Hart","year":"2001","journal-title":"BMJ"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/6\/1467\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:40:05Z","timestamp":1760186405000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/6\/1467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,22]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["ijms20061467"],"URL":"https:\/\/doi.org\/10.3390\/ijms20061467","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,22]]}}}