{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:23:07Z","timestamp":1760239387834,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,24]],"date-time":"2020-10-24T00:00:00Z","timestamp":1603497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K07145","20K07168"],"award-info":[{"award-number":["20K07145","20K07168"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor \u03baB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated that HGF induces RANKL expression in osteoblasts and BMSCs, and investigated the mechanism of induction. We found that HGF and MM cell supernatants induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. In addition, HGF increased phosphorylation of Met and nuclear factor \u03baB (NF-\u03baB) in ST2 cells, MC3T3-E1 cells, or mouse BMSCs. Moreover, Met and NF-\u03baB inhibitors suppressed HGF-induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. These results indicated that HGF promotes RANKL expression in osteoblasts and BMSCs via the Met\/NF-\u03baB signaling pathway, and Met and NF-\u03baB inhibitors suppressed HGF-induced RANKL expression. Our findings suggest that Met and NF-\u03baB inhibitors are potentially useful in mitigating MM-induced bone disease in patients expressing high levels of HGF.<\/jats:p>","DOI":"10.3390\/ijms21217905","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T02:34:54Z","timestamp":1603679694000},"page":"7905","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The HGF\/Met\/NF-\u03baB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells"],"prefix":"10.3390","volume":"21","author":[{"given":"Masanobu","family":"Tsubaki","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiori","family":"Seki","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Takeda","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Chihara","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuuko","family":"Arai","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuusuke","family":"Morii","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan"},{"name":"Department of Pharmacy, Municipal Ikeda Hospital, Ikeda 563-0025, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motohiro","family":"Imano","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-0014, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Satou","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-0014, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunori","family":"Shimomura","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Municipal Ikeda Hospital, Ikeda 563-0025, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3408-0462","authenticated-orcid":false,"given":"Shozo","family":"Nishida","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s00223-017-0351-7","article-title":"New agents in the Treatment of Myeloma Bone Disease","volume":"102","author":"Ring","year":"2018","journal-title":"Calcif. 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