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Early-stage FOP is characterized by recurrent episodes of painful tissue swelling (flare-ups), with numerous proliferation-activated mesenchymal stromal cells (MSCs) subsequently causing HO. However, the mechanisms underlying flare-up progression remain unclear. In this study, we evaluated the proliferation of MSCs obtained from FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to elucidate the mechanisms underlying flare-ups and found that bone morphogenetic protein (BMP)-9 mediated enhanced proliferation by abnormal activation of transforming growth factor (TGF)-\u03b2 signaling pathway in MSCs from FOP-iPSCs. In FOP model mice, elevated BMP-9 levels correlated with elevated phosphorylation of SMAD2\/3 and increased cellular proliferation in the affected tissues, while systemic BMP-9 neutralization and knockout mitigated flare-ups and HO. Thus, BMP-9 aberrantly transduces TGF-\u03b2 signaling and induces fibroproliferation, initiating flare-ups. This study provides novel insights into the development of future FOP therapies.<\/jats:p>","DOI":"10.1038\/s44321-024-00174-3","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T10:53:15Z","timestamp":1733223195000},"page":"112-128","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-\u03b2 signaling"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7957-5381","authenticated-orcid":false,"given":"Chengzhu","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Inada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souta","family":"Motoike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3510-282X","authenticated-orcid":false,"given":"Daisuke","family":"Kamiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyosuke","family":"Hino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3930-8032","authenticated-orcid":false,"given":"Makoto","family":"Ikeya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"174_CR1","doi-asserted-by":"publisher","first-page":"E338","DOI":"10.1073\/pnas.1515397113","volume":"113","author":"S Agarwal","year":"2016","unstructured":"Agarwal S, Loder S, Brownley C, Cholok D, Mangiavini L, Li J, Breuler C, Sung HH, Li S, Ranganathan K et al (2016) Inhibition of Hif1\u03b1 prevents both trauma-induced and genetic heterotopic ossification. 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