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These secretomes in conditioned media from human MSCs (MSC\u2010CM) were previously demonstrated to promote bone and tissue regeneration. Because MSC\u2010CM contain cytokines monocyte chemoattractant protein (MCP)\u20101, insulin growth factor (IGF)\u20101, and vascular endothelial growth factor (VEGF) at relatively higher concentrations than other factors, these cytokines were considered as relevant active factors for tissue regeneration. By mixing the recombinant proteins of MCP\u20101, IGF\u20101, and VEGF, included at the same concentrations in MSC\u2010CM, we prepared cytokine mixtures mimicking MSC\u2010CM and then evaluated its therapeutic effects in a rat MRONJ model. In vitro, cytokine mixtures promoted osteogenic differentiation, migration, and proliferation of rat MSCs. In addition, these maintained osteoclastic function. In vivo, we used a rat MRONJ model to examine therapeutic effects of the cytokine mixtures through intravenous administration. In MSC\u2010CM or cytokine mixture group, open alveolar sockets in 66% or 67% of the rats with MRONJ, respectively, healed with complete soft tissue coverage and socket bones, whereas in the other groups, the exposed necrotic bone with inflamed soft tissue remained. Histological analysis revealed new bone formation and the appearance of osteoclasts in MSC\u2010CM or cytokine mixture group; however, osteoclasts were significantly reduced in the other groups. Thus, we concluded that intravenous administration of cytokine mixtures might be an effective therapeutic modality for treating patients with MRONJ. \u00a9 2017 The Authors <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research<\/jats:p><\/jats:sec>","DOI":"10.1002\/jbm4.10013","type":"journal-article","created":{"date-parts":[[2017,7,25]],"date-time":"2017-07-25T12:44:43Z","timestamp":1500986683000},"page":"69-80","source":"Crossref","is-referenced-by-count":18,"title":["Cytokine Mixtures Mimicking Secretomes From Mesenchymal Stem Cells Improve Medication\u2010Related Osteonecrosis of the Jaw in a Rat Model"],"prefix":"10.1093","volume":"2","author":[{"given":"Kenichi","family":"Ogata","sequence":"first","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology Division of Maxillofacial Diagnostic and Surgical Sciences Faculty of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayu","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology Division of Maxillofacial Diagnostic and Surgical Sciences Faculty of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masafumi","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology Division of Maxillofacial Diagnostic and Surgical Sciences Faculty of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wataru","family":"Katagiri","sequence":"additional","affiliation":[{"name":"Division of Reconstructive Surgery for Oral and Maxillofacial Region Department of Tissue Regeneration and Reconstruction Niigata University Graduate School of Medical and Dental Sciences Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideharu","family":"Hibi","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology Division of Maxillofacial Diagnostic and Surgical Sciences Faculty of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,9,6]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(20000301)88:5<1082::AID-CNCR20>3.0.CO;2-Z"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(20010515)91:10<1956::AID-CNCR1219>3.0.CO;2-F"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.06.037"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.5.6.817"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joms.2014.04.031"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.327.7413.469"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joms.2005.07.010"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.295.24.2833"},{"issue":"3","key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.7326\/0003-4819-145-3-200608010-00023","article-title":"Systematic review: bisphosphonates and osteonecrosis of the jaws","volume":"145","author":"Woo SB","year":"2006","journal-title":"Ann Intern Med"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djm025"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjoms.2009.04.032"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1300"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.37"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1746-160X-7-16"},{"issue":"13","key":"e_1_2_7_16_1","first-page":"5331","article-title":"Long\u2010term cultures of bone marrow\u2010derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation [This article contains errors due to a cross contamination of the cell lines we used. 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