BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling
Abstract Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. Early-stage FOP is characterized by recurrent episodes of painful tissue swelling (flare-ups), with numerous proliferation-activated mesenchymal...
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Springer Nature
2024-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-024-00174-3 |
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| author | Chengzhu Zhao Yoshiko Inada Souta Motoike Daisuke Kamiya Kyosuke Hino Makoto Ikeya |
| author_facet | Chengzhu Zhao Yoshiko Inada Souta Motoike Daisuke Kamiya Kyosuke Hino Makoto Ikeya |
| author_sort | Chengzhu Zhao |
| collection | DOAJ |
| description | Abstract Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. 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)-β 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-β signaling and induces fibroproliferation, initiating flare-ups. This study provides novel insights into the development of future FOP therapies. |
| format | Article |
| id | doaj-art-738410d855c94041bf945288a48a8c04 |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-738410d855c94041bf945288a48a8c042025-01-19T12:34:40ZengSpringer NatureEMBO Molecular Medicine1757-46842024-12-0117111212810.1038/s44321-024-00174-3BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signalingChengzhu Zhao0Yoshiko Inada1Souta Motoike2Daisuke Kamiya3Kyosuke Hino4Makoto Ikeya5Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical UniversityDepartment of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto UniversityAbstract Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. 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)-β 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-β signaling and induces fibroproliferation, initiating flare-ups. This study provides novel insights into the development of future FOP therapies.https://doi.org/10.1038/s44321-024-00174-3Fibrodysplasia Ossificans ProgressiveFlare-UpFibroproliferationPatient-Derived Induced Pluripotent Stem CellsTGF-β Signaling |
| spellingShingle | Chengzhu Zhao Yoshiko Inada Souta Motoike Daisuke Kamiya Kyosuke Hino Makoto Ikeya BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling EMBO Molecular Medicine Fibrodysplasia Ossificans Progressive Flare-Up Fibroproliferation Patient-Derived Induced Pluripotent Stem Cells TGF-β Signaling |
| title | BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling |
| title_full | BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling |
| title_fullStr | BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling |
| title_full_unstemmed | BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling |
| title_short | BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling |
| title_sort | bmp 9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through tgf β signaling |
| topic | Fibrodysplasia Ossificans Progressive Flare-Up Fibroproliferation Patient-Derived Induced Pluripotent Stem Cells TGF-β Signaling |
| url | https://doi.org/10.1038/s44321-024-00174-3 |
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