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.

中文翻译：

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BMP-9 通过 TGF-β 信号传导介导进行性骨化纤维发育不良的纤维增生。


进行性骨化纤维发育不良 （FOP） 是一种罕见的遗传性疾病，表现为软组织进行性异位骨化 （HO）。早期 FOP 的特征是反复发作的疼痛性组织肿胀（发作），随后出现大量增殖激活的间充质基质细胞 （MSCs） 导致 HO。然而，急性发作进展的机制仍不清楚。在这项研究中，我们评估了从 FOP 患者来源的诱导多能干细胞 （FOP-iPSC） 获得的 MSCs 的增殖，以阐明发作的潜在机制，并发现骨形态发生蛋白 （BMP）-9 通过异常激活转化生长因子 （TGF）-β 信号通路介导增殖来自 FOP-iPSCs的 MSCs。在 FOP 模型小鼠中，BMP-9 水平升高与 SMAD2/3 磷酸化升高和受影响组织中细胞增殖增加相关，而全身性 BMP-9 中和和敲除减轻了发作和 HO。因此，BMP-9 异常转导 TGF-β 信号传导并诱导纤维增生，从而引发急性发作。本研究为未来 FOP 疗法的发展提供了新的见解。