{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:24:31Z","timestamp":1783383871963,"version":"3.54.6"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T00:00:00Z","timestamp":1745193600000},"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":["23H03028"],"award-info":[{"award-number":["23H03028"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22bm1123006"],"award-info":[{"award-number":["JP22bm1123006"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["23bm1323001h0001"],"award-info":[{"award-number":["23bm1323001h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP15bm0104001"],"award-info":[{"award-number":["JP15bm0104001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016926","name":"Kyoto University Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016926","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021128","name":"Hyogo Science and Technology Association","doi-asserted-by":"publisher","award":["5024"],"award-info":[{"award-number":["5024"]}],"id":[{"id":"10.13039\/100021128","id-type":"DOI","asserted-by":"publisher"}]},{"name":"iPS Cell Research Fund"},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["202008510007"],"award-info":[{"award-number":["202008510007"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by extraskeletal heterotopic ossification (HO). The underlying mechanism is the aberrant activation of bone morphogenetic protein (BMP) signaling caused by a point mutation in the ACVR1 gene. Although FOP is an ultra-rare disease, its symptoms severely impair patients\u2019 daily activities and quality of life. Furthermore, the HO is also observed in broader clinical contexts, including major surgeries and trauma, highlighting the significance of its study. We have previously reported that rapamycin suppressed Activin-A-triggered progression of cartilage formation in FOP mice. We recently found that the ACVR2B-Fc fusion protein produced by mesenchymal stem\/stromal cells derived from induced pluripotent stem cells (iMSCs) attenuates BMP signaling activated by Activin-A and BMP-9 in FOP patient-derived iMSCs. Transplantation of ACVR2B-Fc-producing iMSCs (iMSC2B-Fc\/Luci) reduces primary HO in FOP mice. In this study, we found that intraperitoneal administration of rapamycin reduced primary HO in a dose-dependent manner in FOP-ACVR1R206H transgenic mice. A low concentration of rapamycin (0.3\u00a0mg\/kg, 5 times\/wk) efficiently suppressed chondrogenesis. The combination of iMSC2B-Fc\/Luci transplantation with low concentration of rapamycin significantly reduced primary and recurrent HO. Rapamycin improved cell survival in transplanted iMSC2B-Fc\/Luci cells by attenuating chemokine secretion, likely resulting in improved ACVR2B-Fc fusion protein production. Our results suggest that combining stem cell therapy and rapamycin can reduce primary HO and surgery-induced HO.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziaf068","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T11:27:01Z","timestamp":1745234821000},"source":"Crossref","is-referenced-by-count":2,"title":["Combined rapamycin and mesenchymal stem\/stromal cells derived from induced pluripotent stem cells-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva"],"prefix":"10.1093","volume":"9","author":[{"given":"Pan","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Department of General Dentistry, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041 ,","place":["China"]},{"name":"Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto 606-8507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Inada","sequence":"additional","affiliation":[{"name":"Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto 606-8507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jos\u00e9","family":"L\u00f3pez-Iniesta","sequence":"additional","affiliation":[{"name":"Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto 606-8507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengzhu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto 606-8507 ,","place":["Japan"]},{"name":"Laboratory of Skeletal 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